ALL - Molecular Biology

Overview

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (144)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
BCR 22q11.23 ALL, CML, PHL, BCR1, D22S11, D22S662 Translocation
-BCR-ABL Translocation in Acute Lymphoblastic Leukaemia
-BCR and Acute Lymphocytic Leukaemia
946
IGH 14q32.33 IGD1, IGH@, IGHJ, IGHV, IGHD@, IGHJ@, IGHV@, IGH.1@, IGHDY1 -IGH and Acute Lymphocytic Leukaemia
224
MLLT10 10p12 AF10 Translocation
-t(10;11)(p13;q14) AF10-PICALM translocation in Acute Leukaemia
-t(10;11)(p12;q23) AF10-MLL translocation in Acute Leukaemia
114
CD34 1q32 -CD34 and Acute Lymphocytic Leukaemia
179
PBX1 1q23 -PBX1 and Acute Lymphocytic Leukaemia
148
KMT2A 11q23 HRX, MLL, MLL1, TRX1, ALL-1, CXXC7, HTRX1, MLL1A, WDSTS, MLL/GAS7, TET1-MLL Translocation
-t(4;11)(q21;q23) MLL-AFF1 in adult acute lymphoblastic leukemia
-t(10;11)(p12;q23) AF10-MLL translocation in Acute Leukaemia
-t(10;11) MLL-TET1 rearrangement in acute leukemias
-t(11;19)(q23;p13.1) MLL-ELL translocation in acute leukaemia
114
RB1 13q14.2 RB, pRb, OSRC, pp110, p105-Rb, PPP1R130 -RB1 and Acute Leukaemias
125
KITLG 12q22 SF, MGF, SCF, FPH2, FPHH, KL-1, Kitl, SHEP7 -KITLG and Acute Lymphocytic Leukaemia
124
MTHFR 1p36.3 -MTHFR and Acute Lymphocytic Leukaemia
117
IKZF1 7p12.2 IK1, LYF1, LyF-1, IKAROS, PPP1R92, PRO0758, ZNFN1A1, Hs.54452 -IKZF1 and Acute Lymphocytic Leukaemia
114
CD33 19q13.3 p67, SIGLEC3, SIGLEC-3 -CD33 and Acute Lymphocytic Leukaemia
92
PICALM 11q14 LAP, CALM, CLTH Translocation
-t(10;11)(p13;q14) AF10-PICALM translocation in Acute Leukaemia
73
CD9 12p13.3 MIC3, MRP-1, BTCC-1, DRAP-27, TSPAN29, TSPAN-29 -CD9 and Acute Lymphocytic Leukaemia
71
PDGFRA 4q12 CD140A, PDGFR2, PDGFR-2, RHEPDGFRA Deletion / Translocation
-FIP1L1-PDGFRA fusion in Leukemia
65
FIP1L1 4q12 Rhe, FIP1, hFip1 Deletion / Translocation
-FIP1L1-PDGFRA fusion in Leukemia
65
CDKN2B 9p21 P15, MTS2, TP15, CDK4I, INK4B, p15INK4b -CDKN2B and Acute Lymphocytic Leukaemia
64
LMO2 11p13 TTG2, RBTN2, RHOM2, RBTNL1 -LMO2 and T-Cell Acute Lymphocytic Leukaemia
61
HLF 17q22 Translocation
-t(17;19)(q22;p13) TCF3-HLF fusion in Acute Lymphoblastic Leukemia
-HLF and Acute Lymphocytic Leukaemia
34
CRLF2 Xp22.3; Yp11.3 CRL2, TSLPR, CRLF2Y -CRLF2 and Acute Lymphocytic Leukaemia
60
ETV6 12p13 TEL, THC5, TEL/ABL Translocation
-t(1;12)(q25;p13) in Leukaemia (AML & ALL)
-t(12;21) in Adult Lyphocytic Leukaemia
35
NOTCH1 9q34.3 hN1, AOS5, TAN1, AOVD1 Translocation
-t(7;9)(q34;q34) in T-Cell Acute Lymphoblastic Leukaemia
-NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL)
43
TLX1 10q24 TCL3, HOX11 -TLX1 and Acute Lymphocytic Leukaemia
37
CD22 19q13.1 SIGLEC2, SIGLEC-2 -CD22 and Acute Lymphocytic Leukaemia
37
TRG 7p14 TCRG, TRG@ -TRG and Acute Lymphoblastic Leukemia
37
ABL1 9q34.1 ABL, JTK7, p150, c-ABL, v-abl, c-ABL1, bcr/abl Translocation
-BCR-ABL Translocation in Acute Lymphoblastic Leukaemia
-NUP214-ABL1 rearrangements in T-Cell Acute Lymphoblastic Leukemia
35
NUP214 9q34.1 CAN, CAIN, N214, p250, D9S46E Translocation
-NUP214-ABL1 rearrangements in T-Cell Acute Lymphoblastic Leukemia
35
RUNX1 21q22.3 AML1, CBFA2, EVI-1, AMLCR1, PEBP2aB, AML1-EVI-1 Translocation
-t(12;21) in Adult Lyphocytic Leukaemia
35
FBXW7 4q31.3 AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 -FBXW7 and Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
34
TCF3 19p13.3 E2A, E47, ITF1, VDIR, TCF-3, bHLHb21 Translocation
-t(17;19)(q22;p13) TCF3-HLF fusion in Acute Lymphoblastic Leukemia
34
SLC19A1 21q22.3 CHMD, FOLT, IFC1, REFC, RFC1 -SLC19A1 and Acute Lymphocytic Leukaemia
30
JAK1 1p32.3-p31.3 JTK3, JAK1A, JAK1B -JAK1 and Acute Lymphocytic Leukaemia
29
TLX3 5q35.1 RNX, HOX11L2 -TLX3 and Acute Lymphocytic Leukaemia
28
IGK 2p12 IGK@ -IGK and Acute Lymphocytic Leukaemia
28
IFNA2 9p22 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Acute Lymphocytic Leukaemia
26
IFNA7 9p22 IFNA-J, IFN-alphaJ -IFNA7 and Acute Lymphocytic Leukaemia
26
IFNA17 9p22 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Acute Lymphocytic Leukaemia
26
TRB 7q34 TCRB, TRB@ Translocation
-t(7;9)(q34;q34) in T-Cell Acute Lymphoblastic Leukaemia
-t(7;19)(q35;p13) in T-cell Acute Lymphoblastic Leukemia
-TRB and Acute Lymphocytic Leukaemia
17
TPMT 6p22.3 -TPMT and Acute Lymphocytic Leukaemia
24
CYP1A1 15q24.1 AHH, AHRR, CP11, CYP1, P1-450, P450-C, P450DX -CYP1A1 and Acute Lymphocytic Leukaemia
24
CD79A 19q13.2 IGA, MB-1 -CD79A and Acute Lymphocytic Leukaemia
24
TAL1 1p32 SCL, TCL5, tal-1, bHLHa17 -TAL1 and Acute Lymphocytic Leukaemia
24
ELL 19p13.1 MEN, ELL1, PPP1R68, C19orf17 Translocation
-ELL and Acute Lymphocytic Leukaemia
-t(11;19)(q23;p13.1) MLL-ELL translocation in acute leukaemia
17
STAM 10p14-p13 STAM1, STAM-1 -STAM and Acute Lymphocytic Leukaemia
22
DHFR 5q14.1 DYR, DHFRP1 -DHFR and Acute Lymphocytic Leukaemia
22
ABL2 1q25.2 ARG, ABLL Translocation
-t(1;12)(q25;p13) in Leukaemia (AML & ALL)
21
P2RY8 Xp22.33; Yp11.3 P2Y8 -P2RY8 and Acute Lymphocytic Leukaemia
20
HLA-DRB1 6p21.3 SS1, DRB1, DRw10, HLA-DRB, HLA-DR1B -HLA-DRB1 and Acute Lymphocytic Leukaemia
20
CD14 5q31.1 -CD14 and Acute Lymphocytic Leukaemia
19
EBF1 5q34 EBF, COE1, OLF1, O/E-1 -EBF1 and Acute Lymphocytic Leukaemia
18
ABCG2 4q22 MRX, MXR, ABCP, BCRP, BMDP, MXR1, ABC15, BCRP1, CD338, GOUT1, CDw338, UAQTL1, EST157481 -ABCG2 and Acute Lymphocytic Leukaemia
18
GALE 1p36-p35 SDR1E1 -GALE and Acute Lymphocytic Leukaemia
18
CEBPE 14q11.2 CRP1, C/EBP-epsilon -CEBPE and Acute Lymphocytic Leukaemia
17
TYMS 18p11.32 TS, TMS, HST422 -TYMS and Acute Lymphocytic Leukaemia
16
LMO1 11p15 TTG1, RBTN1, RHOM1 -LMO1 and T-Cell Leukemia-Lymphoma
16
RFC1 4p14-p13 A1, RFC, PO-GA, RECC1, MHCBFB, RFC140 -RFC1 and Acute Lymphocytic Leukaemia
15
JAK2 9p24 JTK10, THCYT3 -JAK2 mutations in Down syndrome-associated ALL
15
FAS 10q24.1 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Acute Lymphoblastic Leukaemia
15
IL7R 5p13 ILRA, CD127, IL7RA, CDW127, IL-7R-alpha -IL7R and Acute Lymphocytic Leukaemia
14
FHIT 3p14.2 FRA3B, AP3Aase -FHIT and Acute Lymphocytic Leukaemia
14
NR3C1 5q31.3 GR, GCR, GRL, GCCR, GCRST -NR3C1 and Acute Lymphocytic Leukaemia
10
CD1A 1q23.1 R4, T6, CD1, FCB6, HTA1 -CD1A and Acute Lymphocytic Leukaemia
10
SHMT1 17p11.2 SHMT, CSHMT -SHMT1 and Acute Lymphocytic Leukaemia
10
MCL1 1q21 TM, EAT, MCL1L, MCL1S, Mcl-1, BCL2L3, MCL1-ES, bcl2-L-3, mcl1/EAT -MCL1 and Acute Lymphocytic Leukaemia
9
FPGS 9q34.1 -FPGS and Acute Lymphocytic Leukaemia
9
SLCO1B1 12p LST1, HBLRR, LST-1, OATP2, OATPC, OATP-C, OATP1B1, SLC21A6 -SLCO1B1 and Acute Lymphocytic Leukaemia
9
MTHFD1 14q24 MTHFC, MTHFD -MTHFD1 and Acute Lymphocytic Leukaemia
8
STIL 1p32 SIL, MCPH7 -STIL and Adult T-Cell Leukemia-Lymphoma
8
IL15 4q31 IL-15 -IL15 and Acute Lymphocytic Leukaemia
8
RAG2 11p13 RAG-2 -RAG2 and Acute Lymphocytic Leukaemia
8
MLLT1 19p13.3 ENL, LTG19, YEATS1 -MLLT1 and Acute Lymphocytic Leukaemia
8
MTAP 9p21 BDMF, MSAP, DMSFH, LGMBF, DMSMFH, c86fus, HEL-249 -MTAP and Acute Lymphocytic Leukaemia
8
HOXA7 7p15.2 ANTP, HOX1, HOX1A, HOX1.1 -HOXA7 and Acute Lymphocytic Leukaemia
7
CEACAM6 19q13.2 NCA, CEAL, CD66c -CEACAM6 and Acute Lymphocytic Leukaemia
7
HLA-DPB1 6p21.3 DPB1, HLA-DP, HLA-DPB, HLA-DP1B -HLA-DPB1 and Acute Lymphocytic Leukaemia
7
HFE 6p21.3 HH, HFE1, HLA-H, MVCD7, TFQTL2 -HFE and Acute Lymphocytic Leukaemia
7
MLLT3 9p22 AF9, YEATS3 -MLLT3 and Acute Lymphocytic Leukaemia
7
CD79B 17q23 B29, IGB, AGM6 -CD79B and Acute Lymphocytic Leukaemia
7
TCF7L1 2p11.2 TCF3, TCF-3 -TCF7L1 and Acute Lymphocytic Leukaemia
7
RAG1 11p13 RAG-1, RNF74 -RAG1 and Acute Lymphocytic Leukaemia
7
BTG1 12q22 -BTG1 and Acute Lymphocytic Leukaemia
6
OLAH 10p13 SAST, AURA1, THEDC1 -OLAH and Acute Lymphocytic Leukaemia
6
PRAME 22q11.22 MAPE, OIP4, CT130, OIP-4 -PRAME and Acute Lymphocytic Leukaemia
6
CASP8AP2 6q15 CED-4, FLASH, RIP25 -CASP8AP2 and Acute Lymphocytic Leukaemia
6
IDH1 2q33.3 IDH, IDP, IDCD, IDPC, PICD, HEL-216, HEL-S-26 -IDH1 and Acute Lymphocytic Leukaemia
6
MEF2C 5q14.3 DEL5q14.3, C5DELq14.3 -MEF2C and Acute Lymphocytic Leukaemia
6
PMS2 7p22.2 PMSL2, HNPCC4, PMS2CL -PMS2 and Acute Lymphocytic Leukaemia
5
CCNC 6q21 CycC -CCNC and Acute Lymphocytic Leukaemia
5
BCL2L11 2q13 BAM, BIM, BOD -BCL2L11 and Acute Lymphocytic Leukaemia
5
CTLA4 2q33 CD, GSE, GRD4, ALPS5, CD152, CTLA-4, IDDM12, CELIAC3 -CTLA4 and Acute Lymphocytic Leukaemia
5
GAST 17q21 GAS -GAST and Acute Lymphocytic Leukaemia
5
AFF3 2q11.2-q12 LAF4, MLLT2-like -AFF3 and Acute Lymphocytic Leukaemia
5
ABCC2 10q24 DJS, MRP2, cMRP, ABC30, CMOAT -ABCC2 and Acute Lymphocytic Leukaemia
5
TYK2 19p13.2 JTK1, IMD35 -TYK2 and Acute Lymphocytic Leukaemia
5
BIRC7 20q13.3 KIAP, LIVIN, MLIAP, RNF50, ML-IAP -BIRC7 and Acute Lymphocytic Leukaemia
5
PBX3 9q33.3 -PBX3 and Acute Lymphocytic Leukaemia
4
CD83 6p23 BL11, HB15 -CD83 and Acute Lymphocytic Leukaemia
4
SLC29A1 6p21.1 ENT1 -SLC29A1 and Acute Lymphocytic Leukaemia
4
CD3D 11q23 T3D, IMD19, CD3-DELTA -CD3D and Acute Lymphocytic Leukaemia
4
RANBP17 5q34 -RANBP17 and Acute Lymphocytic Leukaemia
4
ROR1 1p31.3 NTRKR1, dJ537F10.1 -ROR1 and Acute Lymphocytic Leukaemia
4
ZNF384 12p12 NP, CIZ, NMP4, CAGH1, ERDA2, TNRC1, CAGH1A -ZNF384 and Acute Lymphocytic Leukaemia
4
TFPT 19q13 FB1, amida, INO80F -TFPT and Acute Lymphocytic Leukaemia
4
ABCC4 13q32 MRP4, MOATB, MOAT-B -ABCC4 and Acute Lymphocytic Leukaemia
4
NOD2 16q21 CD, ACUG, BLAU, IBD1, NLRC2, NOD2B, CARD15, CLR16.3, PSORAS1 -NOD2 and Acute Lymphocytic Leukaemia
4
PTPRG 3p21-p14 PTPG, HPTPG, RPTPG, R-PTP-GAMMA -PTPRG and Acute Lymphocytic Leukaemia
4
TET1 10q21 LCX, CXXC6, bA119F7.1 Translocation
-t(10;11) MLL-TET1 rearrangement in acute leukemias
4
SLC19A2 1q23.3 TC1, THT1, TRMA, THMD1, THTR1 -SLC19A2 and Acute Lymphocytic Leukaemia
4
PTER 10p12 HPHRP, RPR-1 -PTER and Acute Lymphocytic Leukaemia
3
CD69 12p13 AIM, EA1, MLR-3, CLEC2C, GP32/28, BL-AC/P26 -CD69 and Acute Lymphocytic Leukaemia
3
HCK 20q11-q12 JTK9, p59Hck, p61Hck -HCK and Acute Lymphocytic Leukaemia
3
NNAT 20q11.2-q12 Peg5 -NNAT and Acute Lymphocytic Leukaemia
3
MIR126 9q34.3 MIRN126, mir-126, miRNA126 -MicroRNA mir-126 and Acute Lymphocytic Leukaemia
3
CHFR 12q24.33 RNF116, RNF196 -CHFR and Acute Lymphocytic Leukaemia
3
TNFRSF8 1p36 CD30, Ki-1, D1S166E -TNFRSF8 and Acute Lymphocytic Leukaemia
3
CD58 1p13 ag3, LFA3, LFA-3 -CD58 and Acute Lymphocytic Leukaemia
3
TFRC 3q29 T9, TR, TFR, p90, CD71, TFR1, TRFR -TFRC and Acute Lymphocytic Leukaemia
2
CDK2AP1 12q24.31 DOC1, ST19, DORC1, doc-1, p12DOC-1 -CDK2AP1 and Acute Lymphocytic Leukaemia
2
MLLT6 17q21 AF17 -MLLT6 and Acute Lymphocytic Leukaemia
2
GSTO1 10q25.1 P28, SPG-R, GSTO 1-1, GSTTLp28, HEL-S-21 -GSTO1 and Acute Lymphocytic Leukaemia
2
CD55 1q32 CR, TC, DAF, CROM -CD55 and Acute Lymphocytic Leukaemia
2
BLNK 10q23.2-q23.33 bca, AGM4, BASH, LY57, SLP65, BLNK-S, SLP-65 -BLNK and Acute Lymphocytic Leukaemia
2
MNX1 7q36 HB9, HLXB9, SCRA1, HOXHB9 -MNX1 and Acute Lymphocytic Leukaemia
2
LRRC3B 3p24 LRP15 -LRRC3B and Acute Lymphocytic Leukaemia
2
ZNF521 18q11.2 EHZF, Evi3 -ZNF521 and Acute Lymphocytic Leukaemia
2
SERPINC1 1q25.1 AT3, AT3D, ATIII, THPH7 -SERPINC1 and Acute Lymphocytic Leukaemia
2
TTL 2q13 -TTL and Acute Lymphocytic Leukaemia
2
CTNND1 11q11 CAS, p120, CTNND, P120CAS, P120CTN, p120(CAS), p120(CTN) -CTNND1 and Acute Lymphocytic Leukaemia
2
DOK2 8p21.3 p56DOK, p56dok-2 -DOK2 and Acute Lymphocytic Leukaemia
1
ADIPOQ 3q27 ACDC, ADPN, APM1, APM-1, GBP28, ACRP30, ADIPQTL1 -ADIPOQ and Acute Lymphocytic Leukaemia
1
RASSF6 4q13.3 -RASSF6 and Acute Lymphocytic Leukaemia
1
FCRL4 1q21 FCRH4, IGFP2, IRTA1, CD307d -FCRL4 and Acute Lymphocytic Leukaemia
1
ARHGAP26 5q31 GRAF, GRAF1, OPHN1L, OPHN1L1 -ARHGAP26 and Acute Lymphocytic Leukaemia
1
DPH1 17p13.3 DPH2L, OVCA1, DPH2L1 -DPH1 and Acute Lymphocytic Leukaemia
1
SFPQ 1p34.3 PSF, POMP100, PPP1R140 -SFPQ and Acute Lymphocytic Leukaemia
1
CEACAM3 19q13.2 CEA, CGM1, W264, W282, CD66D -CEACAM3 and Acute Lymphocytic Leukaemia
1
TPD52L1 6q22-q23 D53, hD53 -TPD52L1 and Acute Lymphocytic Leukaemia
1
PRTN3 19p13.3 MBN, MBT, NP4, P29, PR3, ACPA, AGP7, NP-4, PR-3, CANCA, C-ANCA -PRTN3 and Acute Lymphocytic Leukaemia
1
ACKR3 2q37.3 RDC1, CXCR7, RDC-1, CMKOR1, CXC-R7, CXCR-7, GPR159 -ACKR3 and Acute Lymphocytic Leukaemia
1
FCGR2B 1q23 CD32, FCG2, CD32B, FCGR2, IGFR2 -FCGR2B and Acute Lymphocytic Leukaemia
1
PNN 14q21.1 DRS, DRSP, SDK3, memA -PNN and Acute Lymphocytic Leukaemia
1
RASSF10 11p15.2 -RASSF10 and Acute Lymphocytic Leukaemia
1
LYL1 19p13.2 bHLHa18 Translocation
-t(7;19)(q35;p13) in T-cell Acute Lymphoblastic Leukemia
BCL2 18q21.3 Bcl-2, PPP1R50 Translocation
-t(14;18)(q32;q21) in Acute Lymphoblastic Leukaemia
AFF1 4q21 AF4, PBM1, MLLT2 Translocation
-t(4;11)(q21;q23) MLL-AFF1 in adult acute lymphoblastic leukemia

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Recurrent Structural Abnormalities

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Latest Publications

Tedeschi PM, Kathari YK, Johnson-Farley N, Bertino JR
Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination.
Cancer Chemother Pharmacol. 2015; 75(6):1247-52 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL).
METHODS: CCRF-CEM (MTAP(-/-)) and Molt4 (MTAP(+/+)) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects.
RESULTS: CEM cells were more sensitive to 6-TG and PDX in vitro than Molt4. In vivo, CEM cells were very sensitive to PDX and 6-TG, whereas Molt4 cells were highly resistant to 6-TG. A well-tolerated combination of PDX and 6-TG achieved significant tumor regression in CEM xenografts.
CONCLUSIONS: The loss of MTAP expression may be therapeutically exploited in T-cell ALL. The combination of 6-TG and PDX, with the inclusion of leucovorin rescue, allows for a safe and effective regimen in MTAP-deficient T-cell ALL.

Kumar KR, Chen W, Koduru PR, Luu HS
Myeloid and lymphoid neoplasm with abnormalities of FGFR1 presenting with trilineage blasts and RUNX1 rearrangement: a case report and review of literature.
Am J Clin Pathol. 2015; 143(5):738-48 [PubMed] Related Publications
OBJECTIVES: Myeloid and lymphoid neoplasms with abnormalities of fibroblast growth factor receptor 1 gene (FGFR1) are a rare and aggressive disease group that harbors translocations of FGFR1 with at least 14 recognized partner genes. We report a case of a patient with a novel t(17;21)(p13;q22) with RUNX1 rearrangement and trilineage blasts.
METHODS: A 29-year-old man with relapsed T-lymphoblastic lymphoma in the cervical nodes showed a myeloproliferative neoplasm in his bone marrow with three separate populations of immunophenotypically aberrant myeloid, T-lymphoid, and B-lymphoid blasts by flow cytometry. Cytogenetic and fluorescent in situ hybridization studies showed unique dual translocations of t(8;13)(p11.2;q12) and t(17;21)(p13;q22) with RUNX1 rearrangement.
RESULTS: The patient was initiated on a mitoxantrone, etoposide, and cytarabine chemotherapy regimen and died of complications of disease 1 month later.
CONCLUSIONS: To our knowledge, this is the first reported case of a myeloid and lymphoid neoplasm with abnormalities of FGFR1 with t(17;21)(p13;q22) and trilineage blasts.

Greaves M
When one mutation is all it takes.
Cancer Cell. 2015; 27(4):433-4 [PubMed] Related Publications
In a recent issue of Nature Genetics, Andersson and colleagues report that MLL fusion alone may be sufficient to spawn an aggressive leukemia in infants. Some other pediatric cancers may share a similar, single, "big-hit" origin, possibly reflecting a critical developmental window of stem cell vulnerability.

Noetzli L, Lo RW, Lee-Sherick AB, et al.
Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.
Nat Genet. 2015; 47(5):535-8 [PubMed] Related Publications
Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

Chen Z, Shojaee S, Buchner M, et al.
Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.
Nature. 2015; 521(7552):357-61 [PubMed] Article available free on PMC after 21/11/2015 Related Publications
B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.

Schnell SA, Ambesi-Impiombato A, Sanchez-Martin M, et al.
Therapeutic targeting of HES1 transcriptional programs in T-ALL.
Blood. 2015; 125(18):2806-14 [PubMed] Article available free on PMC after 30/04/2016 Related Publications
Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo.

Deucher AM, Qi Z, Yu J, et al.
BCL6 expression correlates with the t(1;19) translocation in B-lymphoblastic leukemia.
Am J Clin Pathol. 2015; 143(4):547-57 [PubMed] Related Publications
OBJECTIVES: Study to date suggests that BCL6 protein expression in B-cell neoplasia predominates in germinal center-derived tumors, but less is known regarding its expression in B-lymphoblastic leukemia. Therefore, we designed a comprehensive study of BCL6 expression in B-lymphoblastic leukemia.
METHODS: BCL6, LMO, and HGAL protein expression in B-lymphoblastic leukemia was investigated using immunohistochemical staining of paraffin-embedded bone marrow specimens. Cryptic TCF3(E2A)-PBX1 rearrangements were investigated using interphase fluorescence in situ hybridization.
RESULTS: Six (12%) of 52 B-lymphoblastic leukemias demonstrated BCL6 protein expression, with B-cell lymphoblastic leukemias containing a t(1;19) translocation demonstrating the strongest staining (three of three). Additional t(1;19) cases beyond the screening study showed similar results. Public microarray expression database mining showed that BCL6 messenger RNA expression levels in B-lymphoblastic leukemia correlated with the protein expression findings. Finally, other markers of B-cell development correlated with BCL6 expression in t(1;19) B-lymphoblastic leukemia cases, with LMO2 and HGAL proteins expressed in six (67%) of nine and eight (89%) of nine cases, respectively.
CONCLUSIONS: BCL6 expression is present in a subset of B-lymphoblastic leukemias, especially in cases containing the 1;19 translocation. Investigation for TCF3(E2A)-PBX1 rearrangements may be useful in BCL6-positive B-lymphoblastic leukemia.

McClellan JS, Dove C, Gentles AJ, et al.
Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages.
Proc Natl Acad Sci U S A. 2015; 112(13):4074-9 [PubMed] Article available free on PMC after 30/09/2015 Related Publications
BCR-ABL1(+) precursor B-cell acute lymphoblastic leukemia (BCR-ABL1(+) B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR-ABL1(+) B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU.1. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function. Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR-ABL1(+) B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease. Finally, we determined that myeloid reprogramming may occur to some degree in human patients by identifying primary CD14(+) monocytes/macrophages in BCR-ABL1(+) B-ALL patient samples that possess the BCR-ABL1(+) translocation and clonally recombined VDJ regions.

Geng H, Hurtz C, Lenz KB, et al.
Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia.
Cancer Cell. 2015; 27(3):409-25 [PubMed] Related Publications
Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR(+) ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR(+) ALL.

Olsson L, Johansson B
Ikaros and leukaemia.
Br J Haematol. 2015; 169(4):479-91 [PubMed] Related Publications
The IKZF1 gene at 7p12.2 codes for IKAROS (also termed IKZF1), an essential transcription factor in haematopoiesis involved primarily in lymphoid differentiation. Its importance is underlined by the fact that deregulation of IKAROS results in leukaemia in both mice and men. During recent years, constitutional as well as acquired genetic changes of IKZF1 have been associated with human disease. For example, certain germline single nucleotide polymorphisms in IKZF1 have been shown to increase the risk of some disorders and abnormal expression and somatic rearrangements, mutations and deletions of IKZF1 (ΔIKZF1) have been detected in a wide variety of human malignancies. Of immediate clinical importance is the fact that ΔIKZF1 occurs in 15% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL) and that the presence of ΔIKZF1 is associated with an increased risk of relapse and a poor outcome; in some studies such deletions have been shown to be an independent risk factor also when minimal residual disease data are taken into account. However, cooperative genetic changes, such as ERG deletions and CRLF2 rearrangements, may modify the prognostic impact of ΔIKZF1, for better or worse. This review summarizes our current knowledge of IKZF1 abnormalities in human disease, with an emphasis on BCP ALL.

Peters C, Schrappe M, von Stackelberg A, et al.
Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial.
J Clin Oncol. 2015; 33(11):1265-74 [PubMed] Related Publications
PURPOSE: Although hematopoietic stem-cell transplantation is widely performed in children with high-risk acute lymphoblastic leukemia (ALL), the influence of donor types is poorly understood. Thus, transplantation outcomes were compared in the prospective multinational Berlin-Frankfurt-Muenster (BFM) study group trial: ALL-SCT-BFM 2003 (Allogeneic Stem Cell Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia).
PATIENTS AND METHODS: After conditioning with total-body irradiation and etoposide, 411 children with high-risk ALL received highly standardized stem-cell transplantations during the first or later remissions. Depending on donor availability, grafts originated from HLA-genoidentical siblings or from HLA-matched unrelated donors who were identified and matched by high-resolution allelic typing and were compatible in at least 9 of 10 HLA loci.
RESULTS: Four-year event-free survival (± standard deviation [SD]) did not differ between patients with transplantations from unrelated or sibling donors (0.67 ± 0.03 v 0.71 ± 0.05; P = .405), with cumulative incidences of nonrelapse mortality (± SD) of 0.10 ± 0.02 and 0.03 ± 0.02 (P = .017) and relapse rates (± SD) of 0.22 ± 0.02 and 0.24 ± 0.04 (P = .732), respectively. Among recipients of transplantations from unrelated donors, no significant differences in event-free survival, overall survival, or nonrelapse mortality were observed between 9/10 and 10/10 matched grafts or between peripheral blood stem cells and bone marrow. The absence of chronic graft-versus-host disease had no effect on event-free survival. Engraftment was faster after bone marrow transplantation from siblings and was associated with fewer severe infections and pulmonary complications.
CONCLUSION: Outcome among high-risk pediatric patients with ALL after hematopoietic stem-cell transplantation was not affected by donor type. Standardized myeloablative conditioning produced a low incidence of treatment-related mortality and effective control of leukemia.

Goričar K, Erčulj N, Faganel Kotnik B, et al.
The association of folate pathway and DNA repair polymorphisms with susceptibility to childhood acute lymphoblastic leukemia.
Gene. 2015; 562(2):203-9 [PubMed] Related Publications
Genetic factors may play an important role in susceptibility to childhood acute lymphoblastic leukemia (ALL). The aim of our study was to evaluate the associations of genetic polymorphisms in folate pathway and DNA repair genes with susceptibility to ALL. In total, 121 children with ALL and 184 unrelated healthy controls of Slovenian origin were genotyped for 14 polymorphisms in seven genes of folate pathway, base excision repair and homologous recombination repair (TYMS, MTHFR, OGG1, XRCC1, NBN, RAD51, and XRCC3). In addition, the exon 6 of NBN was screened for the presence of mutations using denaturing high performance liquid chromatography. Twelve polymorphisms were in Hardy-Weinberg equilibrium in controls and their genotype frequencies were in agreement with those reported in other Caucasian populations. Among the investigated polymorphisms and mutations, NBN Glu185Gln significantly decreased susceptibility to B-cell ALL (p=0.037), while TYMS 3R allele decreased susceptibility to T-cell ALL (p=0.011). Moreover, significantly decreased susceptibility to ALL was observed for MTHFR TA (p=0.030) and RAD51 GTT haplotypes (p=0.016). Susceptibility to ALL increased with the increasing number of risk alleles (ptrend=0.007). We also observed significant influence of hOGG-RAD51 and NBN-RAD51 interactions on susceptibility to ALL. Our results suggest that combination of several polymorphisms in DNA repair and folate pathways may significantly affect susceptibility to childhood ALL.

Verduci L, Azzalin G, Gioiosa S, et al.
microRNA-181a enhances cell proliferation in acute lymphoblastic leukemia by targeting EGR1.
Leuk Res. 2015; 39(4):479-85 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is an aggressive cancer that occurs in both children and adults. Starting from an integrated analysis of miRNA/mRNA expression profiles in 20 ALL patients, we identify a negative correlation between miR-181a and EGR1. Coherently, miR-181a over-expression in Jurkat T-ALL cells decreases EGR1 expression, increasing cell proliferation and enhancing the cell-cycle progression from G1 to S phase. We show that EGR1 is a new direct target of miR-181a. Our findings suggest that miR-181a behaves as an onco-miRNA in ALL by down-regulating EGR1.

Zhou M, Wang T, Lai H, et al.
Targeting of the deubiquitinase USP9X attenuates B-cell acute lymphoblastic leukemia cell survival and overcomes glucocorticoid resistance.
Biochem Biophys Res Commun. 2015; 459(2):333-9 [PubMed] Related Publications
Although previous studies attributed a pro-survival role to USP9X in human cancer, how USP9X affects B-cell acute lymphoblastic leukemia (B-ALL) remains unclear. Here, we found that USP9X is overexpressed in B-ALL cell lines and human patients. We investigated the role of USP9X in B-ALL and found that USP9X knockdown significantly reduced leukemic cell growth and increased spontaneous apoptosis, thereby improving survival in immunodeficient mice. These effects are partially mediated by the intrinsic apoptotic pathway, as we found that USP9X-knockdown leukemic cells displayed MCL1 down-regulation, with decreased BCL-2/BCL-XL levels and increased BAX levels. In addition, we demonstrated that USP9X inhibition negatively regulates mTORC1 activity toward its substrate S6K1. Clinically, USP9X inhibition sensitized glucocorticoid-resistant ALL cells to prednisolone; this observation reveals a potential avenue for improving the treatment of drug-resistant relapses. Collectively, our findings suggest that the combination of USP9X targeting and glucocorticoids treatment has attractive utility in B-ALL. This approach represents a potential strategy for promising combination therapies for lymphoid malignancies.

Zhu H, Miao MH, Ji XQ, et al.
miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia.
Biochem Biophys Res Commun. 2015; 459(2):340-5 [PubMed] Related Publications
MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR-664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereas miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR-664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention.

Andersson AK, Ma J, Wang J, et al.
The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
Nat Genet. 2015; 47(4):330-7 [PubMed] Related Publications
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

Mallampati S, Leng X, Ma H, et al.
Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL+ acute lymphoblastic leukemia.
Blood. 2015; 125(19):2968-73 [PubMed] Article available free on PMC after 07/05/2016 Related Publications
Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL(+) acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL(+) ALL.

Luca VC, Jude KM, Pierce NW, et al.
Structural biology. Structural basis for Notch1 engagement of Delta-like 4.
Science. 2015; 347(6224):847-53 [PubMed] Article available free on PMC after 07/05/2016 Related Publications
Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.

Othman MA, Grygalewicz B, Pienkowska-Grela B, et al.
Novel Cryptic Rearrangements in Adult B-Cell Precursor Acute Lymphoblastic Leukemia Involving the MLL Gene.
J Histochem Cytochem. 2015; 63(5):384-90 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
MLL (mixed-lineage-leukemia) gene rearrangements are typical for acute leukemia and are associated with an aggressive course of disease, with a worse outcome than comparable case, and thus require intensified treatment. Here we describe a 69-year-old female with adult B cell precursor acute lymphoblastic leukemia (BCP-ALL) with hyperleukocytosis and immunophenotype CD10- and CD19+ with cryptic MLL rearrangements. G-banding at the time of diagnosis showed a normal karyotype: 46,XX. Molecular cytogenetics using multitude multicolor banding (mMCB) revealed a complex rearrangement of the two copies of chromosome 11. However, a locus-specific probe additionally identified that the MLL gene at 11q23.3 was disrupted, and that the 5' region was inserted into the chromosomal sub-band 4q21; thus the aberration involved three chromosomes and five break events. Unfortunately, the patient died six months after the initial diagnosis from serious infections and severe complications. Overall, the present findings confirm that, by far not all MLL aberrations are seen by routine chromosome banding techniques and that fluorescence in situ hybridization (FISH) should be regarded as standard tool to access MLL rearrangements in patients with BCP-ALL.

Lee ST, Muench MO, Fomin ME, et al.
Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures.
Nucleic Acids Res. 2015; 43(5):2590-602 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large inter-compartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators.

Baughn LB, Biegel JA, South ST, et al.
Integration of cytogenomic data for furthering the characterization of pediatric B-cell acute lymphoblastic leukemia: a multi-institution, multi-platform microarray study.
Cancer Genet. 2015 Jan-Feb; 208(1-2):1-18 [PubMed] Related Publications
It is well documented that among subgroups of B-cell acute lymphoblastic leukemia (B-ALL), the genetic profile of the leukemic blasts has significant impact on prognosis and stratification for therapy. Recent studies have documented the power of microarrays to screen genome-wide for copy number aberrations (CNAs) and regions of copy number-neutral loss of heterozygosity (CNLOH) that are not detectable by G-banding or fluorescence in situ hybridization (FISH). These studies have involved application of a single array platform for the respective cases. The present investigation demonstrates the feasibility and usefulness of integrating array results from multiple laboratories (ARUP, The Children's Hospital of Philadelphia, Cincinnati Children's Hospital Medical Center, and University of Minnesota Medical Center) that utilize different array platforms (Affymetrix, Agilent, or Illumina) in their respective clinical settings. A total of 65 patients enrolled on the Children's Oncology Group (COG) study AALL08B1 were identified for study, as cytogenetic and FISH studies had also been performed on these patients, with a central review of those results available for comparison. Microarray data were first analyzed by the individual laboratories with their respective software systems; raw data files were then centrally validated using NEXUS software. The results demonstrated the added value of integrating multi-platform data with cytogenetic and FISH data and highlight novel findings identified by array including the co-occurrence of low and high risk abnormalities not previously reported to coexist within a clone, novel regions of chromosomal amplification, clones characterized by numerous whole chromosome LOH that do not meet criteria for doubling of a near-haploid, and characterization of array profiles associated with an IKZF1 deletion. Each of these findings raises questions that are clinically relevant to risk stratification.

Chen SY, Yang X, Feng WL, et al.
Organ-specific microenvironment modifies diverse functional and phenotypic characteristics of leukemia-associated macrophages in mouse T cell acute lymphoblastic leukemia.
J Immunol. 2015; 194(6):2919-29 [PubMed] Related Publications
Tumor-associated macrophages are widely studied in solid tumors. The distribution of macrophages in lymph node samples was found to be associated with the prognosis of lymphoma patients. However, the role of macrophages in leukemia and their functional and phenotypic characteristics in hematopoietic malignancies have not been defined. In this study, we examined the distribution and functional and phenotypic characteristics of macrophages in a Notch1-induced mouse model of T cell acute lymphoblastic leukemia (T-ALL). The distribution of macrophages in bone marrow (BM) and spleen, which are proposed as BM and spleen leukemia-associated macrophages (LAMs), were different during the development of leukemia. LAMs stimulated the proliferation of T-ALL cells and had higher migration activity. RNA-sequencing analysis revealed that gene expression profiles of BM and spleen LAMs showed considerable differences. RT-PCR analysis showed that LAMs expressed both M1- and M2-associated phenotypic genes, but they expressed much lower levels of TGF-β1, VEGF-A, and CSF-1 than did tumor-associated macrophages from B16 melanoma. Furthermore, spleen LAMs more potently stimulated the proliferation of T-ALL cells compared with BM LAMs. Moreover, LAMs could be subdivided into M1-like (CD206(-)) and M2-like (CD206(+)) groups. Both CD206(+) and CD206(-) LAMs stimulated the proliferation of T-ALL cells, although CD206(+) LAMs expressed higher levels of most M1- and M2-associated genes. These results suggested the functional and phenotypic characteristics of LAMs, which were modified by organ specific microenvironments. Our results broaden our knowledge about macrophages in malignant microenvironments from solid tumors to leukemia.

Uckun FM, Ma H, Cheng J, et al.
CD22ΔE12 as a molecular target for RNAi therapy.
Br J Haematol. 2015; 169(3):401-14 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
B-precursor acute lymphoblastic leukaemia (BPL) is the most common form of cancer in children and adolescents. Our recent studies have demonstrated that CD22ΔE12 is a characteristic genetic defect of therapy-refractory clones in paediatric BPL and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory paediatric BPL. The purpose of the present study is to evaluate the biological significance of the CD22ΔE12 molecular lesion in BPL and determine if it could serve as a molecular target for RNA interference (RNAi) therapy. Here we report a previously unrecognized causal link between CD22ΔE12 and aggressive biology of human BPL cells by demonstrating that siRNA-mediated knockdown of CD22ΔE12 in primary leukaemic B-cell precursors is associated with a marked inhibition of their clonogenicity. Additionally, we report a nanoscale liposomal formulation of CD22ΔE12-specific siRNA with potent in vitro and in vivo anti-leukaemic activity against primary human BPL cells as a first-in-class RNAi therapeutic candidate targeting CD22ΔE12.

Maude SL, Dolai S, Delgado-Martin C, et al.
Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia.
Blood. 2015; 125(11):1759-67 [PubMed] Article available free on PMC after 12/03/2016 Related Publications
Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile, as well as a high rate of induction failure. Frequent mutations in cytokine receptor and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to interleukin-7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6 of 6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pretreatment levels and compared with control (P < .01) in 5 of 6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P < .01) in 6 of 6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed.

Arora M, Kaul D, Varma N
Functional nature of a novel mutant CYLD observed in pediatric lymphoblastic B-cell leukemia.
Pediatr Blood Cancer. 2015; 62(6):1066-9 [PubMed] Related Publications
The Deubiquitinating enzyme, Cylindromatosis (CYLD), has been established as a crucial regulator of B-cells. The present study was addressed to identify the nature of CYLD-dependent RNomics in patients of pediatric age group with B-ALL. The study revealed the presence of a novel mutant CYLD of 55 kDa in these patients. The mutant CYLD displayed its ability to restrict the cells in G2 phase of cell cycle, down-regulate PLK-1 and block the nuclear translocation of BCL3. Based upon these results, we propose that this mutant CYLD has the capacity to act as a differential marker characteristic of B-cell lymphoblastic leukemia. Pediatr Blood Cancer 2015;62:1066-1069. © 2015 Wiley Periodicals, Inc.

Yang JJ, Landier W, Yang W, et al.
Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.
J Clin Oncol. 2015; 33(11):1235-42 [PubMed] Article available free on PMC after 10/04/2016 Related Publications
PURPOSE: Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.
PATIENTS AND METHODS: The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.
RESULTS: MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.
CONCLUSION: We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

Lund B, Najmi LA, Wesolowska-Andersen A, et al.
Archival bone marrow samples: suitable for multiple biomarker analysis.
Appl Immunohistochem Mol Morphol. 2015; 23(1):71-7 [PubMed] Related Publications
AB Archival samples represent a significant potential for genetic studies, particularly in severe diseases with risk of lethal outcome, such as in cancer. In this pilot study, we aimed to evaluate the usability of archival bone marrow smears and biopsies for DNA extraction and purification, whole genome amplification (WGA), multiple marker analysis including 10 short tandem repeats, and finally a comprehensive genotyping of 33,683 single nucleotide polymorphisms (SNPs) with multiplexed targeted next-generation sequencing. A total of 73 samples from 21 bone marrow smears and 13 bone marrow biopsies from 18 Danish and Norwegian childhood acute lymphoblastic leukemia patients were included and compared with corresponding blood samples. Samples were grouped according to the age of sample and whether WGA was performed or not. We found that measurements of DNA concentration after DNA extraction was dependent on detection method and that spectrophotometry overestimated DNA amount compared with fluorometry. In the short tandem repeat analysis, detection rate dropped slightly with longer fragments. After WGA, this drop was more pronounced. Samples stored for 0 to 3 years showed better results compared with samples stored for 4 to 10 years. Acceptable call rates for SNPs were detected for 7 of 42 archival samples. In conclusion, archival bone marrow samples are suitable for DNA extraction and multiple marker analysis, but WGA was less successful, especially when longer fragments were analyzed. Multiple SNP analysis seems feasible, but the method has to be further optimized.

Zhu XJ, He XL, Wu YP, et al.
[Influence of thymidylate synthase gene polymorphisms on high-dose methotrexate-related toxicities in childhood acute lymphoblastic leukemia].
Zhongguo Dang Dai Er Ke Za Zhi. 2015; 17(1):11-4 [PubMed] Related Publications
OBJECTIVE: To investigate the influence of thymidylate synthase (TS) gene polymorphisms on high-dose methotrexate (HD-MTX)-related toxicities in childhood acute lymphoblastic leukemia (ALL).
METHODS: A total of 73 children who were diagnosed with ALL between March 2011 and March 2013 were included into this study. Genomic DNAs were extracted from their peripheral blood. And then the genotypes of TS 5'-UTR were determined by direct DNA sequencing after PCR. The toxicity response of 73 patients receiving HD-MTX chemotherapy were observed and recorded, and plasma MTX concentrations at 42-48 hours after chemotherapy were measured.
RESULTS: The main HD-MTX-related toxicities of 73 patients receiving HD-MTX chemotherapy were neutropenia, decreased hemoglobin level, thrombocytopenia, liver toxicity, mucosal damage, and gastrointestinal reactions. There were no significant differences in the incidence rate of HD-MTX-related toxicities between children with different TS 5'-UTR genotypes after chemotherapy (P>0.05). TS 5'-UTR genotype was not significantly correlated with plasma MTX concentrations at 42-48 hours after chemotherapy (P>0.05).
CONCLUSIONS: TS gene polymorphisms have no influence on the incidence of HD-MTX-related toxicities in childhood ALL.

Harrison CJ
Blood Spotlight on iAMP21 acute lymphoblastic leukemia (ALL), a high-risk pediatric disease.
Blood. 2015; 125(9):1383-6 [PubMed] Related Publications
Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukemia. Breakage-fusion-bridge cycles followed by chromothripsis and other complex structural rearrangements of chromosome 21 underlie the mechanism giving rise to iAMP21. Patients with iAMP21 are older (median age 9 years), with a low white cell count. They have a high relapse rate when treated as standard risk. Recent studies have shown improved outcome on intensive therapy. Molecular targets for therapy are being sought.

Liu Z, Li F, Zhang B, et al.
Structural basis of plant homeodomain finger 6 (PHF6) recognition by the retinoblastoma binding protein 4 (RBBP4) component of the nucleosome remodeling and deacetylase (NuRD) complex.
J Biol Chem. 2015; 290(10):6630-8 [PubMed] Article available free on PMC after 06/03/2016 Related Publications
The NuRD complex is a conserved transcriptional coregulator that contains both chromatin-remodeling and histone deacetylase activities. Mutations of PHF6 are found in patients with Börjeson-Forssman-Lehmann syndrome, T-cell acute lymphoblastic leukemia, or acute myeloid leukemia. Recently, PHF6 was identified to interact with the NuRD complex, and this interaction is mediated by the RBBP4 component. However, little is known about the molecular basis for the interaction. Here, we present the crystal structure of the complex of the NuRD subunit RBBP4 bound to the PHF6 peptide (residues 162-170). The PHF6 peptide binds to the top surface of the RBBP4 β-propeller. A pair of positively charged residues of the PHF6 peptide insert into the negatively charged pocket of RBBP4, which is critical for the interaction between PHF6 and RBBP4. Corresponding PHF6 mutants impair this interaction in vitro and in vivo. Structural comparison shows that the PHF6-binding pocket overlaps with FOG1 and histone H3 on RBBP4/Nurf55, but it is distinct from the pocket recognizing histone H4, Su(z)12, and MTA1. We further show that the middle disordered region (residues 145-207, containing the RBBP4-binding motif) is sufficient for the transcriptional repression mediated by PHF6 on the GAL4 reporter, and knockdown of RBBP4 diminished the PHF6-mediated repression. Our RBBP4-PHF6 complex structure provides insights into the molecular basis of PHF6-NuRD complex interaction and implicates a role for PHF6 in chromatin structure modulation and gene regulation.

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Cite this page: Cotterill SJ. Acute Lymphocytic Leukemia, Cancer Genetics Web: http://www.cancer-genetics.org/X1205.htm Accessed:

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