CML - Molecular Biology


Chronic myelogenous leukemia (CML) is characterised by the Philadelphia (Ph) chromosome which is seen in over 95% of patients. The Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22, this fuses the ABL1 from chromosome 9 to the BCR gene on chromosome 22. The median age of patients with Ph+ CML is 67 years of age, it can occasionally occur in children (2-3% of all childhood leukaemias).

See also: Chronic Myeloid Leukemia (CML) - clinical resources (24)

Literature Analysis

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

  • Young Adult
  • CRKL
  • NUP98
  • DNA Sequence Analysis
  • Survival Rate
  • Reproducibility of Results
  • Adolescents
  • Benzamides
  • Sirtuin 1
  • Proto-Oncogene Proteins c-bcr
  • K562 Cells
  • Leukemic Gene Expression Regulation
  • Single Nucleotide Polymorphism
  • BCR
  • Pyrimidines
  • Genes, myb
  • Protein Structure, Tertiary
  • Fusion Proteins, bcr-abl
  • JUNB
  • Reference Standards
  • Antineoplastic Agents
  • TET2
  • Pyridazines
  • Sudan
  • Transcription Factors
  • PRDM16
  • eIF-2 Kinase
  • Oligonucleotides, Antisense
  • ASXL1
  • EVI1
  • Reactive Oxygen Species
  • T-Lymphocytes, Cytotoxic
  • Sequence Deletion
  • Protein Kinase Inhibitors
  • Piperazines
  • Proto-Oncogene Proteins
  • Treatment Failure
  • Sensitivity and Specificity
  • Mutation
  • Protein-Tyrosine Kinases
  • Acute Lymphocytic Leukaemia
  • HOXA9
  • Drug Resistance
  • Valproic Acid
  • ZRSR2
  • Chronic Myelogenous Leukemia
  • Philadelphia Chromosome
  • MSI2
  • Polypyrimidine Tract-Binding Protein
  • Seminal Plasma Proteins
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (64)

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'.

BCR 22q11.23 ALL, CML, PHL, BCR1, D22S11, D22S662 Translocation
-BCR-ABL Translocation in Chronic Myeloid Leukaemia
-BCR and Chronic Myelogenous Leukemia
IFNA17 9p22 IFNA, INFA, LEIF2C1, IFN-alphaI -IFNA17 and Chronic Myelogenous Leukemia
IFNA2 9p22 IFNA, INFA2, IFNA2B, IFN-alphaA -IFNA2 and Chronic Myelogenous Leukemia
IFNA7 9p22 IFNA-J, IFN-alphaJ -IFNA7 and Chronic Myelogenous Leukemia
CD34 1q32 -CD34 and Chronic Myelogenous Leukemia
CD33 19q13.3 p67, SIGLEC3, SIGLEC-3 -CD33 and Chronic Myelogenous Leukemia
HOXA9 7p15.2 HOX1, ABD-B, HOX1G, HOX1.7 -HOXA9 and Chronic Myelogenous Leukemia
-t(7;11)(p15;p15) in Chronic Myelogenous Leukaemia
TET2 4q24 MDS, KIAA1546 -TET2 and Chronic Myelomonocytic Leukemia
MECOM 3q26.2 EVI1, MDS1, PRDM3, MDS1-EVI1, AML1-EVI-1 -MECOM and Chronic Myelogenous Leukemia
CRKL 22q11.21 -CRKL and Chronic Myelogenous Leukemia
NUP98 11p15.5 ADIR2, NUP96, NUP196 -NUP98 and Chronic Myelogenous Leukemia
-t(7;11)(p15;p15) in Chronic Myelogenous Leukaemia
GALE 1p36-p35 SDR1E1 -GALE and Chronic Myelogenous Leukemia
LYN 8q13 JTK8, p53Lyn, p56Lyn -LYN and Chronic Myelogenous Leukemia
JUNB 19p13.2 AP-1 -JUNB and Chronic Myelogenous Leukemia
GRB2 17q24-q25 ASH, Grb3-3, MST084, NCKAP2, MSTP084, EGFRBP-GRB2 -GRB2 and Chronic Myelogenous Leukemia
ELN 7q11.23 WS, WBS, SVAS -ELN and Chronic Myelogenous Leukemia
WARS 14q32.31 IFI53, IFP53, GAMMA-2 -WARS and Chronic Myelogenous Leukemia
ASXL1 20q11 MDS, BOPS -ASXL1 and Chronic Myelogenous Leukemia
PRAME 22q11.22 MAPE, OIP4, CT130, OIP-4 -PRAME and Chronic Myelogenous Leukemia
CD36 7q11.2 FAT, GP4, GP3B, GPIV, CHDS7, PASIV, SCARB3, BDPLT10 -CD36 and Chronic Myelogenous Leukemia
MYB 6q22-q23 efg, Cmyb, c-myb, c-myb_CDS -Genes, myb and Chronic Myelogenous Leukemia
CD83 6p23 BL11, HB15 -CD83 and Chronic Myelogenous Leukemia
G6PD Xq28 G6PD1 -G6PD and Chronic Myelogenous Leukemia
IRF8 16q24.1 ICSBP, IRF-8, ICSBP1, IMD32A, IMD32B, H-ICSBP -IRF8 and Chronic Myelogenous Leukemia
PCM1 8p22-p21.3 PTC4 -PCM1 and Chronic Myelogenous Leukemia
IRF4 6p25-p23 MUM1, LSIRF, SHEP8, NF-EM5 -IRF4 Expression in Chronic Myeloid Leukemia
POU2F1 1q24.2 OCT1, OTF1, oct-1B -POU2F1 and Chronic Myelogenous Leukemia
GUSB 7q21.11 BG, MPS7 -GUSB and Chronic Myelogenous Leukemia
SALL4 20q13.2 DRRS, HSAL4, ZNF797, dJ1112F19.1 -SALL4 and Chronic Myelogenous Leukemia
PRDM16 1p36.23-p33 MEL1, LVNC8, PFM13, CMD1LL -PRDM16 and Chronic Myelogenous Leukemia
TRA 14q11.2 IMD7, TCRA, TCRD, TRA@, TRAC -TRA and Chronic Myelogenous Leukemia
CD59 11p13 1F5, EJ16, EJ30, EL32, G344, MIN1, MIN2, MIN3, MIRL, HRF20, MACIF, MEM43, MIC11, MSK21, 16.3A5, HRF-20, MAC-IP, p18-20 -CD59 and Chronic Myelogenous Leukemia
HCK 20q11-q12 JTK9, p59Hck, p61Hck -HCK and Chronic Myelogenous Leukemia
BACH2 6q15 BTBD25 -BACH2 and Chronic Myelogenous Leukemia
ATG7 3p25.3 GSA7, APG7L, APG7-LIKE -ATG7 and Chronic Myelogenous Leukemia
GAB2 11q14.1 -GAB2 and Chronic Myelogenous Leukemia
PDCD5 19q13.11 TFAR19 -PDCD5 and Chronic Myelogenous Leukemia
SLC9A1 1p36.1-p35 APNH, NHE1, LIKNS, NHE-1, PPP1R143 -SLC9A1 and Chronic Myelogenous Leukemia
ZRSR2 Xp22.1 URP, U2AF1L2, U2AF1RS2, U2AF1-RS2 -ZRSR2 and Chronic Myelogenous Leukemia
HDGF 1q23.1 HMG1L2 -HDGF and Chronic Myelogenous Leukemia
ABI2 2q33 ABI-2, ABI2B, AIP-1, AblBP3, argBP1, SSH3BP2, argBPIA, argBPIB -ABI2 and Chronic Myelogenous Leukemia
ARHGAP26 5q31 GRAF, GRAF1, OPHN1L, OPHN1L1 -ARHGAP26 and Chronic Myelogenous Leukemia
MSI2 17q22 MSI2H -MSI2 and Chronic Myelogenous Leukemia
SRSF2 17q25.1 SC35, PR264, SC-35, SFRS2, SFRS2A, SRp30b -SRSF2 and Chronic Myelogenous Leukemia
XPO1 2p15 emb, CRM1, exp1 -XPO1 and Chronic Myelogenous Leukemia
CD55 1q32 CR, TC, DAF, CROM -CD55 and Chronic Myelogenous Leukemia
IRF2 4q34.1-q35.1 IRF-2 -IRF2 and Chronic Myelogenous Leukemia
U2AF1 21q22.3 RN, FP793, U2AF35, U2AFBP, RNU2AF1 -U2AF1 and Chronic Myelogenous Leukemia
CBLB 3q13.11 Cbl-b, RNF56, Nbla00127 -CBLB and Chronic Myelogenous Leukemia
PDCD1LG2 9p24.2 B7DC, Btdc, PDL2, CD273, PD-L2, PDCD1L2, bA574F11.2 -PDCD1LG2 and Chronic Myelogenous Leukemia
CEACAM3 19q13.2 CEA, CGM1, W264, W282, CD66D -CEACAM3 and Chronic Myelogenous Leukemia
ZNF384 12p12 NP, CIZ, NMP4, CAGH1, ERDA2, TNRC1, CAGH1A -ZNF384 and Chronic Myelogenous Leukemia
ESPL1 12q ESP1, SEPA -ESPL1 and Chronic Myelogenous Leukemia
HLA-DPB1 6p21.3 DPB1, HLA-DP, HLA-DPB, HLA-DP1B -HLA-DPB1 and Chronic Myelogenous Leukemia
CBLC 19q13.2 CBL-3, RNF57, CBL-SL -CBLC and Chronic Myelogenous Leukemia
RPN1 3q21.3 OST1, RBPH1 -RPN1 and Chronic Myelogenous Leukemia
PLCD1 3p22-p21.3 NDNC3, PLC-III -PLCD1 and Chronic Myelogenous Leukemia
FGFR1OP 6q27 FOP -FGFR1OP and Chronic Myelogenous Leukemia
MAFG 17q25.3 hMAF -MAFG and Chronic Myelogenous Leukemia
RNF217-AS1 6q22.33 STL -STL and Chronic Myelogenous Leukemia
HOXC11 12q13.3 HOX3H -HOXC11 and Chronic Myelogenous Leukemia
ENDOU 12q13.1 P11, PP11, PRSS26 -ENDOU and Chronic Myelogenous Leukemia
PRTN3 19p13.3 MBN, MBT, NP4, P29, PR3, ACPA, AGP7, NP-4, PR-3, CANCA, C-ANCA -PRTN3 and Chronic Myelogenous Leukemia
ABL1 9q34.1 ABL, JTK7, p150, c-ABL, v-abl, c-ABL1, bcr/abl Translocation
-BCR-ABL Translocation in Chronic Myeloid Leukaemia

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

Latest Research Publications

Li C, Wang Y, Xu D, et al.
E255K and G250E mutation appearing in a patient with e19a2 chronic myeloid leukemia resistant to imatinib.
Clin Lab. 2015; 61(1-2):183-6 [PubMed] Related Publications
BACKGROUND: Chronic myeloid leukemia (CML) with the e19a2 transcript coding for p230 is a rare disease. ABL1 kinase domain mutations in CML with the e19a2 rearrangement were seldom reported.
METHODS: The clinical characteristics of a 45-year-old Chinese female CML patient with e19a2 BCR/ABL1 transcript were described. The mutation on the ABL gene exons was determined by sequencing the cDNA of the μ-BCR-ABL fusion product.
RESULTS: This patient developed an acquired resistance associated with two p-BCR/ABL1 mutations (E255K and G250E) during treatment with imatinib.
CONCLUSIONS: Here, we report a CML patient with e19a2 transcripts, carrying E255K and G250E mutation and experience of nilotinib treatment. The μ-BCR/ABL1 mutation should be investigated after imatinib treatment failure.

Grimes HL, Meyer SE
A 2-way miRror of red blood cells and leukemia.
Blood. 2015; 125(8):1202-3 [PubMed] Related Publications
In this issue of Blood, the articles by Shaham et al and Wang et al are the first to identify microRNA 486 (miR-486) as a requisite oncomiR and credible therapeutic target in myeloid leukemia of Down syndrome (ML-DS) and chronic myeloid leukemia (CML) by showing that these 2 leukemias co-opt miR-486 functions in normal erythroid progenitor progrowth and survival activity.

Wang LS, Li L, Li L, et al.
MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors.
Blood. 2015; 125(8):1302-13 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) are key regulators of hematopoietic cell differentiation and may contribute to altered growth of leukemic stem cells. Using microarray-based miRNA profiling, we found that miRNA 486 (miR-486) is significantly upregulated in chronic myeloid leukemia (CML) compared with normal CD34(+) cells, particularly in the megakaryocyte-erythroid progenitor population. miR-486-5p expression increased during erythroid differentiation of both CML and normal CD34(+) cells. Ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD34(+) cells, whereas miR-486-5p inhibition suppressed normal CD34(+) cell growth in vitro and in vivo and inhibited erythroid differentiation and erythroid cell survival. The effects of miR-486-5p on hematopoietic cell growth and survival are mediated at least in part via regulation of AKT signaling and FOXO1 expression. Using gene expression and bioinformatics analysis, together with functional screening, we identified several novel miR-486-5p target genes that may modulate erythroid differentiation. We further show that increased miR-486-5p expression in CML progenitors is related to both kinase-dependent and kinase-independent mechanisms. Inhibition of miR-486-5p reduced CML progenitor growth and enhanced apoptosis following imatinib treatment. In conclusion, our studies reveal a novel role for miR-486-5p in regulating normal hematopoiesis and of BCR-ABL-induced miR-486-5p overexpression in modulating CML progenitor growth, survival, and drug sensitivity.

Gniot M, Lewandowski K, Ratajczak B, et al.
Transient presence of clonal chromosomal aberrations in Ph-negative cells in patients with chronic myeloid leukemia remaining in deep molecular response on tyrosine kinase inhibitor treatment.
Cancer Genet. 2014 Oct-Dec; 207(10-12):503-10 [PubMed] Related Publications
Advancements in treatment of chronic myeloid leukemia (CML) turned this formerly fatal neoplasm into a manageable chronic condition. Therapy with tyrosine kinase inhibitors (TKIs) often leads to significant reduction of disease burden, known as the deep molecular response (DMR). Herein, we decided to analyze the cohort of CML patients treated in our center with TKIs, who obtain and retain DMR for a period longer than 24 months. The aim of the study was to evaluate the frequency of clonal cytogenetic aberrations in Philadelphia-negative (Ph-) cells in patients with DMR during TKI treatment. The analyzed data was obtained during routine molecular and cytogenetic treatment monitoring, using G-banded trypsin and Giemsa stain (GTG) karyotyping and reverse transcription quantitative PCR. We noticed that approximately 50% of patients (28 of 55) in DMR had, at some follow-up point, transient changes in the karyotype of their Ph- bone marrow cells. In 9.1% of cases (5 of 55), the presence of the same aberrations was observed at different time points. The most frequently appearing aberrations were monosomies of chromosomes 19, 20, 21, and Y. Statistical analysis suggests that the occurrence of such abnormalities in CML patients correlates with the TKI treatment time.

Bănescu C, Trifa AP, Voidăzan S, et al.
CAT, GPX1, MnSOD, GSTM1, GSTT1, and GSTP1 genetic polymorphisms in chronic myeloid leukemia: a case-control study.
Oxid Med Cell Longev. 2014; 2014:875861 [PubMed] Free Access to Full Article Related Publications
Oxidative damage at the DNA level may be promoted by high levels of reactive oxygen species (ROS), leading to genomic instability and increased neoplastic risk. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) enzymes are implicated in the prevention of DNA damage by ROS. The aim of the study was to investigate the relationships between CAT C262T, GPX1 Pro198Leu, MnSOD Ala16Val, GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms and the risk of CML. No association was observed between CML and variant genotypes of GPX1, MnSOD, GSTM1, and GSTT1 polymorphisms in any of the investigated cases. Our study suggests that the homozygous variant genotype of the GSTP1 Ile105Val gene polymorphisms may be associated with the risk of developing CML (OR = 2.5; 95% CI = 1.08-5.7; P value = 0.02), while the heterozygous genotype of the CAT C262T polymorphism seems to have a protective effect against CML (OR = 0.59, 95% CI = 0.39-0.89, P value = 0.01). In most cases, no association was found between laboratory parameters and prognostic factors and the variant genotype of investigated gene polymorphisms. We concluded that CAT, GPX, MnSOD, GSTM1, and GSTT1 gene polymorphisms are not associated with the risk of CML. Variant genotype of the GSTP1 Ile105Val gene polymorphisms may contribute to the risk of developing CML.

Erba HP
Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: importance of achieving treatment-free remission.
Am J Hematol. 2015; 90(3):242-9 [PubMed] Related Publications
Imatinib was the first BCR-ABL1 tyrosine kinase inhibitor (TKI) developed for the treatment of patients with chronic myeloid leukemia (CML); subsequently, the introduction of more potent BCR-ABL1 TKIs has raised expectations regarding the speed and depth of response. This review discusses how molecular monitoring is being used as an integral part of the treatment regimen to achieve improved outcomes in patients with CML. The long-term prognostic implications of achieving early molecular response to TKI therapy and the feasibility of maintaining treatment-free remission will also be discussed in light of current clinical data.

Mian AA, Rafiei A, Haberbosch I, et al.
PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation.
Leukemia. 2015; 29(5):1104-14 [PubMed] Related Publications
Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the 'gatekeeper' mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL-T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.

Han L, Wang Y, Guo X, et al.
Downregulation of MDR1 gene by cepharanthine hydrochloride is related to the activation of c-Jun/JNK in K562/ADR cells.
Biomed Res Int. 2014; 2014:164391 [PubMed] Free Access to Full Article Related Publications
The purpose of the study was to determine the signal transduction mechanism of cepharanthine hydrochloride (CH) on reversing tumor multidrug resistance. RT-PCR and Western blot analysis were used to determine the effects of CH on the expression of MDR1 mRNA and P-glycoprotein in K562/ADR cells when CH was used alone and combined with SP600125, a JNK inhibitor, to explore the effects of CH on JNK pathway. Western blot analysis was used to determine the effects of CH on c-Jun protein expression and phosphorylation, to explore the regulating effects of CH on c-Jun and phosphorylated c-Jun (p-c-Jun) proteins. Our results showed that the inhibitory effect of CH on MDR1 mRNA increased with the concentrations of CH (5.0, 10.0, and 20.0 μM) and the inhibitory effects of CH on MDR1 mRNA and P-glycoprotein increased with the incubation time of CH (0, 12, 24, 36, and 48 hours). The inhibitory effect was weakened after CH combined with SP600125. The expressions of c-Jun and p-c-Jun proteins increased with the incubation time of CH (0, 6, 12, and 24 hours). These findings suggest that CH downregulated the expressions of MDR1 mRNA and P-glycoprotein in a time and concentration manner; the mechanism may be mediated via activating c-Jun/JNK pathway.

Machova Polakova K, Kulvait V, Benesova A, et al.
Next-generation deep sequencing improves detection of BCR-ABL1 kinase domain mutations emerging under tyrosine kinase inhibitor treatment of chronic myeloid leukemia patients in chronic phase.
J Cancer Res Clin Oncol. 2015; 141(5):887-99 [PubMed] Related Publications
PURPOSE: Here, we studied whether amplicon next-generation deep sequencing (NGS) could improve the detection of emerging BCR-ABL1 kinase domain mutations in chronic phase chronic myeloid leukemia (CML) patients under tyrosine kinase inhibitor (TKI) treatment and discussed the clinical relevance of such sensitive mutational detection.
METHODS: For NGS data evaluation including extraction of biologically relevant low-level variants from background error noise, we established and applied a robust and versatile bioinformatics approach.
RESULTS: Results from a retrospective longitudinal analysis of 135 samples of 15 CML patients showed that NGS could have revealed emerging resistant mutants 2-11 months earlier than conventional sequencing. Interestingly, in cases who later failed first-line imatinib treatment, NGS revealed that TKI-resistant mutations were already detectable at the time of major or deeper molecular response. Identification of emerging mutations by NGS was mirrored by BCR-ABL1 transcript level expressed either fluctuations around 0.1 %(IS) or by slight transcript level increase. NGS also allowed tracing mutations that emerged during second-line TKI therapy back to the time of switchover. Compound mutants could be detected in three cases, but were not found to outcompete single mutants.
CONCLUSIONS: This work points out, that next-generation deep sequencing, coupled with a robust bioinformatics approach for mutation calling, may be just in place to ensure reliable detection of emerging BCR-ABL1 mutations, allowing early therapy switch and selection of the most appropriate therapy. Further, prospective assessment of how to best integrate NGS in the molecular monitoring and clinical decision algorithms is warranted.

Gambacorti-Passerini CB, Donadoni C, Parmiani A, et al.
Recurrent ETNK1 mutations in atypical chronic myeloid leukemia.
Blood. 2015; 125(3):499-503 [PubMed] Related Publications
Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders.

Agarwal A, Mackenzie RJ, Besson A, et al.
BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein.
Blood. 2014; 124(22):3260-73 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
Recent studies have revealed that p27, a nuclear cyclin-dependent kinase (Cdk) inhibitor and tumor suppressor, can acquire oncogenic activities upon mislocalization to the cytoplasm. To understand how these antagonistic activities influence oncogenesis, we dissected the nuclear and cytoplasmic functions of p27 in chronic myeloid leukemia (CML), a well-characterized malignancy caused by the BCR-ABL1 tyrosine kinase. p27 is predominantly cytoplasmic in CML and nuclear in normal cells. BCR-ABL1 regulates nuclear and cytoplasmic p27 abundance by kinase-dependent and -independent mechanisms, respectively. p27 knockdown in CML cell lines with predominantly cytoplasmic p27 induces apoptosis, consistent with a leukemogenic role of cytoplasmic p27. Accordingly, a p27 mutant (p27(CK-)) devoid of Cdk inhibitory nuclear functions enhances leukemogenesis in a murine CML model compared with complete absence of p27. In contrast, p27 mutations that enhance its stability (p27(T187A)) or nuclear retention (p27(S10A)) attenuate leukemogenesis over wild-type p27, validating the tumor-suppressor function of nuclear p27 in CML. We conclude that BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. These findings suggest that cytoplasmic mislocalization of p27 despite BCR-ABL1 inhibition by tyrosine kinase inhibitors may contribute to drug resistance, and effective therapeutic strategies to stabilize nuclear p27 must also prevent cytoplasmic mislocalization.

Schwaab J, Knut M, Haferlach C, et al.
Limited duration of complete remission on ruxolitinib in myeloid neoplasms with PCM1-JAK2 and BCR-JAK2 fusion genes.
Ann Hematol. 2015; 94(2):233-8 [PubMed] Related Publications
Rearrangements of chromosome band 9p24 are known to be associated with JAK2 fusion genes, e.g., t(8;9)(p22;p24) with a PCM1-JAK2 and t(9;22)(p24;q11) with a BCR-JAK2 fusion gene, respectively. In association with myeloid neoplasms, the clinical course is aggressive, and in absence of effective conventional treatment options, long-term remission is usually only observed after allogeneic stem cell transplantation (ASCT). With the discovery of inhibitors of the JAK2 tyrosine kinase and based on encouraging in vitro and in vivo data, we treated two male patients with myeloid neoplasms and a PCM1-JAK2 or a BCR-JAK2 fusion gene, respectively, with the JAK1/JAK2 inhibitor ruxolitinib. After 12 months of treatment, both patients achieved a complete clinical, hematologic, and cytogenetic response. Non-hematologic toxicity was only grade 1 while no hematologic toxicity was observed. However, remission in both patients was only short-term, with relapse occurring after 18 and 24 months, respectively, making ASCT indispensable in both cases. This data highlight (1) the ongoing importance of cytogenetic analysis for the diagnostic work-up of myeloid neoplasms as it may guide targeted therapy and (2) remission under ruxolitinib may only be short-termed in JAK2 fusion genes but it may be an important bridging therapy prior to ASCT.

Illert AL, Albers C, Kreutmair S, et al.
Grb10 is involved in BCR-ABL-positive leukemia in mice.
Leukemia. 2015; 29(4):858-68 [PubMed] Related Publications
The SH2-containing adaptor protein Grb10 was first identified in a yeast screen as a new binding partner for BCR-ABL and associates with BCR-ABL in a tyrosine-dependent manner. However, its function in BCR-ABL-mediated leukemogenesis in vivo is still unknown. Here we describe an important role of Grb10 in BCR-ABL-induced leukemia by using a versatile system for efficient oncogene expression and simultaneous Grb10 knockdown from a single vector. Primary bone marrow (BM) cells coexpressing Grb10-miR/BCR-ABL showed a significant decrease in colony formation and cell cycle progression. Transplantation of Grb10miR/BCR-ABL- or control-miR/BCR-ABL- transduced BM leads to a CML/B-ALL-like phenotype with significantly delayed disease onset and progression resulting in prolonged overall survival in Grb10-miR-transplanted mice. Methylcellulose experiments exhibit additive effects of imatinib treatment and Grb10 knockdown. Cell cycle analysis suggests an anti-proliferative effect of Grb10 knockdown in BCR-ABL(+) primary BM cells. However, Grb10 abrogation was not capable of completely abolishing the BCR-ABL-induced disease. Our findings were confirmed in the human BCR-ABL(+) cell line K562, where we demonstrate reduced viability, cell cycle progression and induction of apoptosis by stable Grb10 microRNA expression. Taken together, our results suggest that Grb10 knockdown in vivo leads to impaired proliferation, longer survival and reduced colony formation, suggesting an important role of Grb10 in BCR-ABL-mediated leukemogenesis.

Link-Lenczowska D, Sacha T, Zawada M, et al.
[Atypical BCR-ABL transcripts in patients with chronic myeloid leukemia--the scheme for the diagnosis and monitoring of minimal residual disease].
Przegl Lek. 2014; 71(5):258-62 [PubMed] Related Publications
More than 95% of patients with detected translocation t(9;22), is characterized by the fusion between exons e13 or e14 of BCR gene, which are located in major breakpoint cluster region (M-bcr) and exon a2 of ABL gene. These fusions are described as b2a2 (e13a2) and b3a2 (e14a2). Other fusions of exons e1, e6, e8, e12, e19, e20 of BCR gene with exons a2 or a3 of ABL gene occur very rarely and lead to formation of so called unusual fusion BCR-ABL genes. The aim of this study is to describe long-term observations of the occurrence and routine procedure in the diagnosis of atypical variants of the fusion gene BCR-ABL in a population of patients with chronic myeloid leukemia (CML). It was found that the vast majority of patients with detected BCR-ABL transcripts were b3a2 and b2a2. Other detected variants, which are described as rare were: e1a2, b2a3, b3a3, c3a2, e6a2, e6a3. At the stage of diagnosis as well as during monitoring of the effects of treatment, molecular methods which are based on polymerase chain reaction were used (multiplex RT-PCR, nested RT-PCR, RQ-PCR). Multiplex RT-PCR reaction gave possibility to detect variants of the fusion BCR-ABL gene in one reaction and was crucial in the selection of appropriate test used for further monitoring of the disease and the effectiveness of treatment. This paper proposes a scheme for dealing with the diagnosis and monitoring of minimal residual disease (MRD) in patients with CML treated with tyrosine kinase inhibitors (TKIs) in the presence of rare fusion of the BCR and ABL genes.

Xishan Z, Xianjun L, Ziying L, et al.
The malignancy suppression role of miR-23a by targeting the BCR/ABL oncogene in chromic myeloid leukemia.
Cancer Gene Ther. 2014; 21(9):397-404 [PubMed] Related Publications
The aim of this study was to investigate the role and mechanism of miR-23a in the regulation of BCR/ABL and to provide a new prognostic biomarker for chronic myeloid leukemia (CML). The expression levels of miR-23a and BCR/ABL were assessed in 42 newly diagnosed CML patients, 37 CML patients in first complete remission and 25 healthy controls. Quantitative real-time PCR, western blot analysis and colony formation assay were used to evaluate changes induced by overexpression or inhibition of miR-23a or BCR/ABL. MiR-23a mimic or negative control mimic was transfected into a CML cell line (K562) and two lung cancer cell lines (H157 and SKMES1) using Lipofectamine 2000, and the cells were used for real-time reverse transcription-PCR (RT-PCR) and western blot analysis. We found that the downregulation of miR-23a expression was a frequent event in both leukemia cell lines and primary leukemic cells from patients with de novo CML. The microarray results showed that most of the CML patients expressed high levels of BCR/ABL and low levels of miR-23a. Real-time RT-PCR and western blot analysis showed that the BCR/ABL levels in miR-23a-transfected cells were lower than those in the control groups. Ectopic expression of miR-23a in K562 cells led to cellular senescence. Moreover, when K562 cells were treated with 5-aza-2'-deoxycytidine, a DNA methylation inhibitor, BCR/ABL expression was upregulated, which indicates epigenetic silencing of miR-23a in leukemic cells. BCR/ABL and miR-23a expressions were inversely related to CML, and BCR/ABL expression was regulated by miR-23a in leukemic cells. The epigenetic silencing of miR-23a led to derepression of BCR/ABL expression, and consequently contributes to CML development and progression.

Schmidt M, Rinke J, Schäfer V, et al.
Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status.
Leukemia. 2014; 28(12):2292-9 [PubMed] Related Publications
To study clonal evolution in chronic myeloid leukemia (CML), we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome (Ph)-negative and Ph-positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in myeloid disorders. Ph-negative clones were analyzed in 14 patients who developed clonal cytogenetic abnormalities in Ph-negative cells during treatment with tyrosine kinase inhibitors (TKI). Mutations were detected in 6/14 patients (43%) affecting the genes DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2. In two patients, the mutations were also found in corresponding Ph-positive diagnostic samples. To further investigate Ph-positive clones, 15 randomly selected CML patients at diagnosis were analyzed. Somatic mutations additional to BCR-ABL were found in 5/15 patients (33%) affecting ASXL1, DNMT3A, RUNX1 and TET2. Analysis of individual hematopoietic colonies at diagnosis revealed that most mutations were part of the Ph-positive clone. In contrast, deep sequencing of subsequent samples during TKI treatment revealed one DNMT3A mutation in Ph-negative cells that was also present in Ph-positive cells at diagnosis, implying that the mutation preceded the BCR-ABL rearrangement. In summary, BCR-ABL-independent gene mutations were frequently found in Ph-negative and Ph-positive clones of CML patients and may be considered as important cofactors in the clonal evolution of CML.

Huet S, Cony-Makhoul P, Heiblig M, et al.
Major molecular response achievement in CML Patients can be predicted by BCR-ABL1/ABL1 or BCR-ABL1/GUS ratio at an earlier time point of follow-up than currently recommended.
PLoS One. 2014; 9(9):e106250 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
Recent studies demonstrate that early molecular response to tyrosine-kinase inhibitors is strongly predictive of outcome in chronic myeloid leukemia patients and that early response landmarks may identify patients at higher risk for transformation who would benefit from an early switch to second-line therapy. In this study, we evaluated the ability of the control gene GUS to identify relevant thresholds for known therapeutic decision levels (BCR-ABL1/ABL1IS  = 10% and 0.1%). We then defined the most relevant cut-offs for early molecular response markers (transcript level at 3 months, halving time and log reduction between diagnosis and 3 months of treatment) using GUS or ABL1. We demonstrated that, although both control genes could be used (in an equivalent way) to accurately assess early molecular response, the BCR-ABL1/GUS level at diagnosis is impacted by the higher GUS copy number over-expressed in CML cells, thus negatively impacting its ability to completely replace ABL1 at diagnosis. Furthermore, we pointed out, for the first time, that it would be helpful to monitor BCR-ABL1 levels at an earlier time point than that currently performed, in order to assess response to first-line tyrosine-kinase inhibitors and consider a potential switch of therapy as early as possible. We evaluated this optimal time point as being 19 days after the start of treatment in our cohort.

Radich J
Structure, function, and resistance in chronic myeloid leukemia.
Cancer Cell. 2014; 26(3):305-6 [PubMed] Related Publications
Chronic myeloid leukemia (CML) is effectively treated by tyrosine kinase inhibitors (TKIs). Rarely, CML cases develop TKI resistance through acquisition of compound mutations. In this issue of Cancer Cell, Zabriskie and colleagues study how structural changes caused by compound mutations cause clinically relevant changes in TKI sensitivity.

Lucas CM, Harris RJ, Giannoudis A, et al.
Low leukotriene B4 receptor 1 leads to ALOX5 downregulation at diagnosis of chronic myeloid leukemia.
Haematologica. 2014; 99(11):1710-5 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
ALOX5 is implicated in chronic myeloid leukemia development in mouse leukemic stem cells, but its importance in human chronic myeloid leukemia is unknown. Functional ALOX5 was assessed using an LTB4 ELISA and ALOX5, and LTB4R1 mRNA expression was determined via a TaqMan gene expression assay. LTB4R1 and 5-LOX protein levels were assessed by cell surface flow cytometry analysis. At diagnosis ALOX5 was below normal in both blood and CD34(+) stem cells in all patients. On treatment initiation, ALOX5 levels increased in all patients except those who were destined to progress subsequently to blast crisis. LTB4 levels were increased despite low ALOX5 expression, suggesting that the arachidonic acid pathway is functioning normally up to the point of LTB4 production. However, the LTB4 receptor (BLT1) protein in newly diagnosed patients was significantly lower than after a period of treatment (P<0.0001). The low level of LTB4R1 at diagnosis explains the downregulation of ALOX5. In the absence of LTB4R1, the arachidonic acid pathway intermediates (5-HEPTE and LTA4) negatively regulate ALOX5. ALOX5 regulation is aberrant in chronic myeloid leukemia patients and may not be important for the development of the disease. Our data suggest caution when extrapolating mouse model data into human chronic myeloid leukemia.

Millot F, Guilhot J, Baruchel A, et al.
Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study.
Blood. 2014; 124(15):2408-10 [PubMed] Related Publications
Studies in adults have shown that an early molecular response to imatinib predicts clinical outcome in chronic myeloid leukemia (CML). We investigated the impact of the BCR-ABL1 transcript level measured 3 months after starting imatinib in a cohort of 40 children with CML. Children with a BCR-ABL1/ABL ratio higher than 10% at 3 months after the start of imatinib had a larger spleen size and a higher white blood cell count compared with those with BCR-ABL1/ABL ≤10%. Children with BCR-ABL1/ABL ≤10% 3 months after starting imatinib had higher rates of complete cytogenetic response and major molecular response at 12 months compared with those with BCR-ABL1/ABL >10%. With a median follow-up of 71 months (range, 22-96 months), BCR-ABL1/ABL ≤10% correlated with better progression-free survival. Thus, early molecular response at 3 months predicts outcome in children treated with imatinib for CML. This trial was registered at as #NCT00845221.

Gao G, Xu N, Yin C, et al.
[Correlation between point mutation in ABL kinase and clinical outcome of chronic myeloid leukemia patients].
Zhonghua Xue Ye Xue Za Zhi. 2014; 35(8):703-7 [PubMed] Related Publications
OBJECTIVE: To analyze the association of different types of ABL tyrosine point mutations and imatinib resistance to probe the relation between ABL tyrosine point mutations and the prognosis of patients with chronic myeloid leukemia (CML).
METHODS: Nested reverse transcriptasepolym erase chain reaction was performed on samples from 70 patients to amplify the ABL kinase domain. Then, the amplified product was purified and sequenced in both direction. The homologous analysis was performed in combination of clinical data.
RESULTS: The ABL domain point mutations were detected in 32 patients (45.7%) including 16 patients in chronic phase (CP), 6 patients in accelerated phase(AP)and 10 patients in blast phase (BP), which were detected as T315I, E255K, C475Y, Y253H, G321W, G250E, F317L, E258K, F359V, E459K and F311I, respectively. Sokal score with intermediate and high risk and Ph+ chromosome with complex karyotype were important risk factors for ABL domain point mutations. The 5-year overall survival (OS) was not significantly different between the patients with or without ABL domain point mutations (78.1% vs 84.2%, P=0.985), while the 5-year cumulative event-free survival (EFS) of two groups were 34.4% and 68.4% (P=0.034), respectively. The rate of complete cytogenetic response was higher in patients treated with allogenic hematopetic stem cell transplantation (allo-HSCT) compared with patients merely treated with second-generation tyrosine kinase inhibitors or chemotherapeutics (P=0.001).
CONCLUSION: Patients with ABL domain point mutations had poor efficacy and prognosis compared to those without ABL domain point mutations. Detection of ABL domain point mutations in CML-CP was helpful for the adjustment of therapeutic options and improvement of prognosis. And allo-HSCT was a more effective therapy for patients with advanced phase.

Zabriskie MS, Eide CA, Tantravahi SK, et al.
BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.
Cancer Cell. 2014; 26(3):428-42 [PubMed] Article available free on PMC after 08/09/2015 Related Publications
Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph(+)) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph(+) leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.

Zhang JF, Liu XL, Lin YD, et al.
[Bioinformatic analysis of chronic myeloid leukemia progression and preliminary experimental verification].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014; 22(4):909-13 [PubMed] Related Publications
This study was aimed to explore the progression mechanism of chronic myeloid leukemia, so as to provide the new molecular markers for evaluation of CML clinical outcome and selection of treatment. The microarray data of genes related with progression from different phase of chronic myeloid leukemia (CML) were collected from public data depository GEO (Gene expression datasets). SAM analysis, fold change filtering, cross comparison were used to analyze the data and identify different genes. Moreover, MeV and pSTIING sofewares were used to analyze the key differential genes and signal pathways. At last, Q-PCR were used to confirm the predicted key gene. The results indicated that after comparison, 9 genes were differentially expressed from AP to BC, and the integrin-mediated cell adhesion , focal adhesion, regulation of actin cytoskeleton were the principal pathways during CML progression. Network construction analysis found that AP-related genes or pathways may be the original signals; and MLLT4, WDR35 and EPHB4 were the key genes for CML progression. EPHB4 was confirmed by Q-PCR in CML BC patients and CP patients. It is concluded that MLLT4, WDR35, EPHB4, integrin-mediated cell adhesion, focal adhesion and regulation of actin cytoskeleton are the principal genes and pathways during CML progression.

Yin XF, Ma QL, Mu QT, et al.
Outcome prediction by the transcript level of BCR-ABL at 3 months in patients with chronic myeloid leukemia treated with imatinib--a single institution historical experience.
Leuk Res. 2014; 38(10):1191-8 [PubMed] Related Publications
The BCR-ABL transcript level (≤ 10%) at 3 months after tyrosine kinase inhibitors can predict long term outcome in the patients with chronic myeloid leukemia in chronic phase (CML-CP). However, the significance of transcript level was still not determined in different risk groups of patients. A total of 299 patients with CML-CP were enrolled and stratified according to prior interferon-α (IFN) treatment, age, and interval time between diagnosis and imatinib treatment to investigate the prediction value of BCR-ABL transcript level for overall survival (OS), event-free survival (EFS), progression-free survival (PFS). Univariate and multivariate analysis proved that BCR-ABL transcript level at 3 months were associated with the treatment outcome. However, in the patients with prior IFN treatment, younger age, and longer interval between diagnosis and IM treatment, the predictive value of transcript value remain obscure in terms of EFS, PFS and OS, respectively, as well as cumulative incidence of PCyR, CCR, MMR and CMR. In conclusion, the transcript level of BCR-ABL at 3 months could serve as a predictive parameter, but should be used with caution.

Yaya K, Hind D, Meryem Q, et al.
Single nucleotide polymorphisms of multidrug resistance gene 1 (MDR1) and risk of chronic myeloid leukemia.
Tumour Biol. 2014; 35(11):10969-75 [PubMed] Related Publications
Multidrug resistance gene 1 (MDR1) is known for its involvement in the detoxification through the active transport of toxic compounds from diverse origins outside the cells. These compounds could cause injury to cell DNA, which might lead in cancer like chronic myeloid leukemia (CML). Individual inherited genetic differences related to polymorphism in detoxification enzymes could be an important factor not only in carcinogen metabolism but also in susceptibility of cancer. The present study aimed to investigate the association of three single nucleotide polymorphisms (SNPs) of the MDR1 gene in the susceptibility of CML. We successively have determined the genotype profiles of 1236 C>T (exon 12); 2677 G>T (exon 21), and 3435 C>T (exon 26) SNPs by PCR-RFLP in 89 patients and 99 unrelated healthy controls. Logistic regression was used to assess the effect of each SNP on the development of CML. Interestingly, in exon 12, the 1236 TT was significantly associated with the susceptibility of CML when compared to the wild type 1236 CC (OR 2.7; 95% CI 1-7.32, p = 0.041). Additionally, the recessive model 1236 TT vs. 1236 CC/CT showed a risk of 3.3 fold (p = 0.011) with CML. In exon 26, the 3435 CT genotype was associated with a reduced risk of CML (OR 0.5; 95% CI 0.3-1, p = 0.042). In exon 21, the 2677 GT genotype seems to have a protective effect (OR 0.6; 95% CI 0.32-1.1, p = 0.074). Diplolotypes analysis has demonstrated no effect in susceptibility of CML, but 1236 CT/3435 CC and 1236 CC/2677 GT were associated with a protective effect. The haplotypes analysis showed no particular trend (global association p = 0.33). Our findings demonstrate that 1236 TT in exon 12 might contribute in the susceptibility of CML, while the 3435 CT in exon 26 as well as 1236 CT/3435 CC and 1236 CC/2677 GT combinations might be protective factors.

Saraconi G, Severi F, Sala C, et al.
The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas.
Genome Biol. 2014; 15(7):417 [PubMed] Article available free on PMC after 08/09/2015 Related Publications
BACKGROUND: The AID/APOBECs are deaminases that act on cytosines in a diverse set of pathways and some of them have been linked to the onset of genetic alterations in cancer. Among them, APOBEC1 is the only family member to physiologically target RNA, as the catalytic subunit in the Apolipoprotein B mRNA editing complex. APOBEC1 has been linked to cancer development in mice but its oncogenic mechanisms are not yet well understood.
RESULTS: We analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA. We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene. Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro.
CONCLUSIONS: Our findings suggest that the ability of APOBEC1 to trigger genetic alterations represents a major layer in its oncogenic potential. Such APOBEC1-induced mutator phenotypes could play a role in the onset of esophageal adenocarcinomas. APOBEC1 could be involved in cancer promotion at the very early stages of carcinogenesis, as it is highly expressed in Barrett's esophagus, a condition often associated with esophageal adenocarcinoma.

Saudy NS, Fawzy IM, Azmy E, et al.
BMI1 gene expression in myeloid leukemias and its impact on prognosis.
Blood Cells Mol Dis. 2014; 53(4):194-8 [PubMed] Related Publications
BACKGROUND: BMI1 is a polycomb group (PcG) protein and is overexpressed in leukemia. It plays a key role in the self-renewal of stem cells. Leukemic cells lacking BMI1 underwent proliferation arrest and showed signs of differentiation and apoptosis.
AIM: This study was aimed to investigate the expression and impact of BMI1 in myeloid leukemias. Expression levels of BMI1 in 100 acute myeloid leukemia (AML), 100 chronic myeloid leukemia (CML) patients and 20 healthy controls were measured by real time quantitative polymerase chain reaction (RQ-PCR).
RESULTS: The results showed that the expression of BMI1 was significantly higher in AML and CML versus control subjects (p<0.001 for both). The 2-year overall and disease free survival rates were significantly lower in patients expressing higher BMI1. Multivariate analysis showed that BMI1 was independent prognostic factor for OS for AML cases (p=0.015, HR=3.204, 95% CI=1.250-8.212). Accelerated and blastic phases in CML cases expressed higher BMI1 than chronic phase (p<0.001).
CONCLUSION: We concluded that detecting BMI1 is helpful for predicting the survival in AML patients and monitoring the aggressiveness and progression in patients with CML.

He H, He G, Wang T, et al.
Methylenetetrahydrofolate reductase gene polymorphisms contribute to acute myeloid leukemia and chronic myeloid leukemia susceptibilities: evidence from meta-analyses.
Cancer Epidemiol. 2014; 38(5):471-8 [PubMed] Related Publications
PURPOSE: The expression of methylenetetrahydrofolate reductase (MTHFR) is associated with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Most studies have linked the common functional C677T and A1298C polymorphisms of the MTHFR gene and susceptibility to AML and CML, but the results were not consistent. The aim of the present study was to derive a more precise estimation of the relationship.
METHODS: Meta-analyses assessing the association of MTHFR C677T and A1298C variations with AML and CML were conducted. Eligible articles were identified from the PubMed and EMBASE databases. All statistical analyses were conducted using Review Manager Software.
RESULTS: 10 and 10 studies were included in the meta-analysis about the role of C677T polymorphism on the AML and CML risks, respectively; 6 and 4 studies were included about the role of A1298C polymorphism on the AML and CML risks, respectively. Overall, both the C677T and A1298C polymorphisms were significantly associated with CML risk under the recessive model (P=0.04, OR=1.35, 95% CI=1.02-1.79 for C677T and P=0.003, OR=2.17, 95% CI=1.29-3.63 for A1298C). In addition, the risk of CML was higher in 1298CC genotype carriers than in 1298AA genotype carriers (P=0.004, OR=2.17, 95%=1.28-3.69). Conversely, the overall data failed to indicate a significant association of C677T or A1298C polymorphisms with AML risk under any model.
CONCLUSIONS: The findings provide evidence that C677T and A1298C polymorphisms are risk factors for CML risk.

Griffiths M, Patton SJ, Grossi A, et al.
Conversion, correction, and International Scale standardization: results From a Multicenter External Quality Assessment Study for BCR-ABL1 testing.
Arch Pathol Lab Med. 2015; 139(4):522-9 [PubMed] Related Publications
CONTEXT: Monitoring BCR-ABL1 expression levels relative to clinically validated response criteria on the International Scale (IS) is vital in the optimal management of patients with chronic myeloid leukemia, yet significant variability remains across laboratories worldwide.
OBJECTIVE: To assess method performance, interlaboratory precision, and different IS standardization modalities in representative laboratories performing routine BCR-ABL1 testing.
DESIGN: Fifteen blinded test specimens with 5-level nominal BCR-ABL1 to ABL1 IS percentage ratios ranging from 5% to 0.0005% and 4-level secondary IS reference panels, the ARQ IS Calibrator Panels, were tested by relative quantitative polymerase chain reaction in 15 laboratories in 5 countries. Both raw and IS percentage ratios calculated by using local conversion factors (CFs) or analytic correction parameters (CPs) were collected and analyzed.
RESULTS: A total of 670 valid positive results were generated. BCR-ABL1 detection was associated with variable ABL1 quality metric passing rates (P < .001) and reached at least 0.01% in 13 laboratories. Intralaboratory precision was within 2.5-fold for all sample levels combined with a relative mean difference greater than 5-fold across laboratories. International Scale accuracy was increased by using both the CF and CP standardization methods. Classification agreement for major molecular response status was 90% after CF conversion and 93% after CP correction, with precision improved by 3-fold for the CP method.
CONCLUSIONS: Despite preanalytic and analytic differences between laboratories, conversion and correction are effective IS standardization methods. Validated secondary reference materials can facilitate global diffusion of the IS without the need to perform sample exchange and improve the accuracy and precision of BCR-ABL1 quantitative measurements, including at low levels of residual disease.

Wang J, Xu H, Zhang H, et al.
CIAPIN1 targets Na+/H+ exchanger 1 to mediate K562 chronic myeloid leukemia cells' differentiation via ERK1/2 signaling pathway.
Leuk Res. 2014; 38(9):1117-25 [PubMed] Related Publications
CIAPIN1 (cytokine-induced antiapoptotic inhibitor 1) was recently identified as an essential downstream effector of the Ras signaling pathway. However, its potential role in regulating myeloid differentiation remains unclear. In this study, we found depletion of CIAPIN1 by shRNAs led to granulocytic differentiation of K562 cells. Meanwhile, the decrease of NHE1 and up-regulation of phosphorylated ERK1/2 were observed after CIAPIN1 depletion. Interestingly, targeted inhibition of NHE1 further promoted the differentiation of K562 cells with CIAPIN1 silencing. Accordingly, ectopic expression of NHE1 reversed this phenotype. Furthermore, ERK1/2 inhibition with the chemical inhibitor, PD98059, abolished CIAPIN1 silencing-induced differentiation of K562 cells after NHE1 inhibition. Thus, our results revealed important mechanism that CIAPIN1 targeted NHE1 to mediate differentiation of K562 cells via ERK1/2 pathway. Our findings implied CIAPIN1 and NHE1 could be new targets in developing therapeutic strategies against leukemia.

Recurring Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
BCR-ABL Translocation in Chronic Myeloid LeukaemiaTranslocationABL1 (9q34.1)BCR (22q11.23)

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.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

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