Gene Summary

Gene:ASXL1; additional sex combs like transcriptional regulator 1
Aliases: MDS, BOPS
Summary:This gene is similar to the Drosophila additional sex combs gene, which encodes a chromatin-binding protein required for normal determination of segment identity in the developing embryo. The protein is a member of the Polycomb group of proteins, which are necessary for the maintenance of stable repression of homeotic and other loci. The protein is thought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of other genes. The protein encoded by this gene functions as a ligand-dependent co-activator for retinoic acid receptor in cooperation with nuclear receptor coactivator 1. Mutations in this gene are associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:putative Polycomb group protein ASXL1
Source:NCBIAccessed: 20 August, 2015


What does this gene/protein do?
Show (17)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 20 August 2015 using data from PubMed using criteria.

Literature Analysis

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

  • Chromosome Aberrations
  • World Health Organization
  • Transcription
  • Leukemic Gene Expression Regulation
  • Childhood Cancer
  • Chromosome 20
  • Genetic Predisposition
  • Single Nucleotide Polymorphism
  • Transcription Factors
  • Young Adult
  • Disease Progression
  • Gene Expression Profiling
  • Polycomb Repressive Complex 2
  • Myeloproliferative Disorders
  • Adolescents
  • Myelodysplastic Syndromes
  • Sex Factors
  • DNA Methylation
  • Genotype
  • Mutation
  • Chronic Myelomonocytic Leukemia
  • Karyotyping
  • Neoplasm Proteins
  • Chronic Myelogenous Leukemia
  • Oncogenes
  • DNA (Cytosine-5-)-Methyltransferase
  • ASXL1
  • Cohort Studies
  • Protein Processing, Post-Translational
  • Isocitrate Dehydrogenase
  • Acute Myeloid Leukaemia
  • Core Binding Factor Alpha 2 Subunit
  • Cancer Gene Expression Regulation
  • Nuclear Proteins
  • Neoplastic Cell Transformation
  • DNA Mutational Analysis
  • Epigenetics
  • JAK2
  • Risk Factors
  • Age Factors
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: ASXL1 (cancer-related)

Angelova S, Spassov B, Nikolova V, et al.
Tsitol Genet. 2015 May-Jun; 49(3):25-32 [PubMed] Related Publications
The aim of our study was 1) to define if the amplification of c-MYC, MLL and RUNX1 genes is related to the progressive changes of the karyotype in patients with AML and MDS with trisomy 8, 11 and 21 (+8, +11 and +21) in bone marrow and 2) can that amplification be accepted as part of the clonal evolution (CE). Karyotype analysis was performed in 179 patients with AML or MDS with the different chromosomal aberrations (CA) aged 16-81. The findings were distributed as follow: initiating balanced CA (n = 60), aneuploidia (n = 55), unbalanced CA (n = 64). Amplification of c-MYC, MLL and RUNX1 genes by means of fluorescence in situ hybridization (FISH) was found in 35% (7 out of 20) of AML and MDS patients with +8, +11 u +21 as single CA in their karyotype; in 63.6% of pts (7 out of 11)--with additional numerical or structural CA and in 75% (9 out of 12)--with complex karyotype. We assume that the amplification of the respective chromosomal regions in patients with +8, +11 and +21 is related to CE. Considering the amplification as a factor of CE, we established 3 patterns of karyotype development depending on the type of the initiating CA in it. Significant statistical differences were found between the three patterns regarding the karyotype distribution in the different stages of progression (p < 0.001).

Yoshizato T, Dumitriu B, Hosokawa K, et al.
Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.
N Engl J Med. 2015; 373(1):35-47 [PubMed] Related Publications
BACKGROUND: In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia.
METHODS: We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients.
RESULTS: Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients.
CONCLUSIONS: Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).

Shirai CL, Ley JN, White BS, et al.
Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo.
Cancer Cell. 2015; 27(5):631-43 [PubMed] Article available free on PMC after 11/05/2016 Related Publications
Heterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼ 11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq). Integration with human RNA-seq datasets determined that common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and recurrently mutated MDS and acute myeloid leukemia-associated genes. These findings support the hypothesis that mutant U2AF1 alters downstream gene isoform expression, thereby contributing to abnormal hematopoiesis in patients with MDS.

Schinke C, Giricz O, Li W, et al.
IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.
Blood. 2015; 125(20):3144-52 [PubMed] Article available free on PMC after 14/05/2016 Related Publications
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML.

Baba M, Hata T, Tsushima H, et al.
The level of bone marrow WT1 message is a useful marker to differentiate myelodysplastic syndromes with low blast percentage from cytopenia due to other reasons.
Intern Med. 2015; 54(5):445-51 [PubMed] Related Publications
OBJECTIVE: Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that transform to acute leukemia. Distinguishing MDS from other cytopenias is sometimes difficult even for trained hematologists. WT1, the gene mutated in Wilms' tumor, was found expressed in acute myeloid leukemia and MDS. The amount of WT1 in peripheral blood and bone marrow (BM) is low in low-risk MDS subtypes, and is high in high-risk MDS subtypes. However, the role of WT1 in the differential diagnosis between MDS and other diseases showing cytopenia has not been fully addressed. The present study evaluated whether WT1 expression level can assist in the differential diagnosis of MDS from other cytopenias.
METHODS: The amount of WT1 message was evaluated among 56 MDS patients and 47 patients with cytopenia for various other reasons (cytopenia VR) at the Nagasaki University Hospital.
RESULTS: The level of WT1 was significantly related to the percentage of blasts in BM among MDS cases, and the type of French-American-British classification of MDS; refractory anemia (RA) cases showed significantly lower WT1 level than patients with RA with excess blasts. WT1 level was significantly related to the prognostic risk categories of MDS by the International Prognostic Scoring System (IPSS) and the revised IPSS. Although the blast percentage in the BM of RA and cytopenia VR were both less than 5%, there was a significant difference in the level of WT1 between MDS and cytopenia VR.
CONCLUSION: WT1 might be a good marker to differentiate low blast percentage MDS and cytopenia VR.

Walter MJ
What came first: MDS or AML?
Blood. 2015; 125(9):1357-8 [PubMed] Related Publications
In this issue of Blood, Lindsley et al have identified a set of 8 genes that, when mutated, appear to be highly specific for secondary acute myeloid leukemia (AML) vs de novo AML.

Patnaik MM, Wassie EA, Lasho TL, et al.
Blast transformation in chronic myelomonocytic leukemia: Risk factors, genetic features, survival, and treatment outcome.
Am J Hematol. 2015; 90(5):411-6 [PubMed] Related Publications
Among 274 patients with chronic myelomonocytic leukemia (CMML) and followed for a median of 17.1 months, blast transformation (BT) occurred in 36 (13%). On multivariable analysis, risk factors for BT were presence of circulating blasts (HR 5.7; 95% CI 2.8-11.9) and female gender (HR 2.6; 95% CI 1.3-5.1); the results remained unchanged when analysis was restricted to CMML-1. ASXL1/SRSF2/SF3B1/U2AF1/SETBP1 mutational frequencies were not significantly different between time of CMML diagnosis and BT. Median survival post-BT was 4.7 months (5-year survival 6%) and better with allogeneic stem cell transplant (SCT) (14.3 months vs. 4.3 months for chemotherapy vs. 0.9 months for supportive care; P = 0.03). Neither karyotype nor mutational status was independently associated with risk of BT or post-BT survival. We conclude that female patients with CMML and those with circulating blasts are at a higher risk of BT. Post-BT survival is dismal and our observations suggest consideration of allogeneic SCT prior to BT.

Skalska-Sadowska J, Januszkiewicz-Lewandowska D, Derwich K, et al.
Ph-negative isolated myeloid sarcoma with NPM1 gene mutation in adolescent with Ph-positive chronic myeloid leukemia in remission after treatment with allogeneic bone marrow transplantation and imatinib mesylate.
Pediatr Blood Cancer. 2015; 62(6):1070-1 [PubMed] Related Publications
Few patients in remission of Ph-positive chronic myelogenous leukemia (CML) develop Ph-negative MDS/AML, usually with clonal cytogenetic abnormalities. Isolated Ph-negative myeloid sarcoma (MS) is presented here as a form of such disorder, different from Ph-positive MS establishing CML relapse in blastic phase. We describe 11-year-old male who developed Ph-negative isolated MS with NPM1 mutation, remaining in complete molecular remission of Ph-positive chronic myeloid leukemia treated with allo-HSCT in first chronic phase and with imatinib and donor lymphocyte infusion in molecular relapse. The possible mechanisms of the tumor formation are reviewed with stress on importance of comprehensive molecular/cytogenetic evaluations.

Estécio MR, Maddipoti S, Bueso-Ramos C, et al.
RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype.
Br J Haematol. 2015; 169(3):344-51 [PubMed] Related Publications
Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re-expression. Furthermore, relapse-free survival of non-inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.

Hyoda T, Tsujioka T, Nakahara T, et al.
Rigosertib induces cell death of a myelodysplastic syndrome-derived cell line by DNA damage-induced G2/M arrest.
Cancer Sci. 2015; 106(3):287-93 [PubMed] Related Publications
A multi-kinase inhibitor, rigosertib (ON 01910.Na) has recently been highlighted as a novel type of anti-cancer agent for the treatment of the myelodysplastic syndromes (MDS), but its action mechanisms remain to be clarified. We investigated the in vitro effects of rigosertib on an MDS-derived cell line MDS-L and a myeloid leukemia cell line HL-60. Rigosertib suppressed the proliferation of both HL-60 and MDS-L cells and induced apoptosis by inhibition of the PI3 kinase/Akt pathway. As the effects on cell cycle, rigosertib treatment promoted the phosphorylation of histone H2AX and led to the DNA damage-induced G2/M arrest. In addition, an immunofluorescence staining study demonstrated the abnormal localization of aurora A kinase, suggesting that rigosertib causes perturbation of spindle assembly and deregulated mitotic patterns towards cell cycle arrest and apoptosis. We also found that rigosertib exerted growth inhibitory effects on two lymphoid cell lines, Jurkat and Ramos. We further examined the molecular pathways influenced by rigosertib from the gene expression profiling data of MDS-L cells and found a possible involvement of rigosertib treatment in the upregulation of the genes related to microtubule kinetics and the downregulation of the mRNA degradation system. The gene set enrichment analysis showed the suppression of "nonsense-mediated mRNA decay (NMD)" as the most significantly affected gene set. These data provide a new aspect and a potential utility of rigosertib for the treatment of refractory hematopoietic malignancies.

Ok CY, Patel KP, Garcia-Manero G, et al.
Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases.
Leuk Res. 2015; 39(3):348-54 [PubMed] Related Publications
In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. Of therapy-related cases, mutations were detected in 71.4% of t-AML versus 39.3% t-MDS (p=0.0127). TP53 was the most common mutated gene in t-MDS (35.7%) as well as t-AML (33.3%), significantly higher than de novo MDS (17.7%) (p=0.0410) and de novo AML (12.8%) (p=0.0020). t-AML showed more frequent PTPN11 but less NPM1 and FLT3 mutations than de novo AML. In summary, t-MDS/AML shows a mutation profile different from their de novo counterparts. TP53 mutations are highly and similarly prevalent in t-MDS and t-AML but mutations in genes other than TP53 were more frequent in t-AML than t-MDS. The molecular genetic profiling further expands our understanding in this group of clinically aggressive yet heterogeneous myeloid neoplasms.

Jawhar M, Schwaab J, Schnittger S, et al.
Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event.
Leukemia. 2015; 29(5):1115-22 [PubMed] Related Publications
To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte-macrophage colony-forming progenitor cells (CFU-GM) in patients with KIT D816V(+) indolent SM (ISM, n=4), smoldering SM (SSM, n=2), aggressive SM (ASM, n=1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5) and ASM-AHNMD (n=7). All patients with (A)SM-AHNMD (n=12) carried 1-4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V(+) single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0-95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V(-). These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD,

Garzon R, Volinia S, Papaioannou D, et al.
Expression and prognostic impact of lncRNAs in acute myeloid leukemia.
Proc Natl Acad Sci U S A. 2014; 111(52):18679-84 [PubMed] Article available free on PMC after 14/05/2016 Related Publications
Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged ≥60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P < 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [P < 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival.

Ko M, An J, Pastor WA, et al.
TET proteins and 5-methylcytosine oxidation in hematological cancers.
Immunol Rev. 2015; 263(1):6-21 [PubMed] Related Publications
DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting, and X-chromosome inactivation. Cancer cells display highly dysregulated DNA methylation profiles characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands that presumably lead to genome instability and aberrant expression of tumor suppressor genes or oncogenes. The recent discovery of ten-eleven-translocation (TET) family dioxygenases that oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) in DNA has led to profound progress in understanding the mechanism underlying DNA demethylation. Among the three TET genes, TET2 recurrently undergoes inactivating mutations in a wide range of myeloid and lymphoid malignancies. TET2 functions as a bona fide tumor suppressor particularly in the pathogenesis of myeloid malignancies resembling chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) in human. Here we review diverse functions of TET proteins and the novel epigenetic marks that they generate in DNA methylation/demethylation dynamics and normal and malignant hematopoietic differentiation. The impact of TET2 inactivation in hematopoiesis and various mechanisms modulating the expression or activity of TET proteins are also discussed. Furthermore, we also present evidence that TET2 and TET3 collaborate to suppress aberrant hematopoiesis and hematopoietic transformation. A detailed understanding of the normal and pathological functions of TET proteins may provide new avenues to develop novel epigenetic therapies for treating hematological malignancies.

Kitamura T, Inoue D, Okochi-Watanabe N, et al.
The molecular basis of myeloid malignancies.
Proc Jpn Acad Ser B Phys Biol Sci. 2014; 90(10):389-404 [PubMed] Article available free on PMC after 14/05/2016 Related Publications
Myeloid malignancies consist of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN). The latter two diseases have preleukemic features and frequently evolve to AML. As with solid tumors, multiple mutations are required for leukemogenesis. A decade ago, these gene alterations were subdivided into two categories: class I mutations stimulating cell growth or inhibiting apoptosis; and class II mutations that hamper differentiation of hematopoietic cells. In mouse models, class I mutations such as the Bcr-Abl fusion kinase induce MPN by themselves and some class II mutations such as Runx1 mutations induce MDS. Combinations of class I and class II mutations induce AML in a variety of mouse models. Thus, it was postulated that hematopoietic cells whose differentiation is blocked by class II mutations would autonomously proliferate with class I mutations leading to the development of leukemia. Recent progress in high-speed sequencing has enabled efficient identification of novel mutations in a variety of molecules including epigenetic factors, splicing factors, signaling molecules and proteins in the cohesin complex; most of these are not categorized as either class I or class II mutations. The functional consequences of these mutations are now being extensively investigated. In this article, we will review the molecular basis of hematological malignancies, focusing on mouse models and the interfaces between these models and clinical findings, and revisit the classical class I/II hypothesis.

Wong TN, Ramsingh G, Young AL, et al.
Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.
Nature. 2015; 518(7540):552-5 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Therapy-related acute myeloid leukaemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy. There are several features that distinguish t-AML from de novo AML, including a higher incidence of TP53 mutations, abnormalities of chromosomes 5 or 7, complex cytogenetics and a reduced response to chemotherapy. However, it is not clear how prior exposure to cytotoxic therapy influences leukaemogenesis. In particular, the mechanism by which TP53 mutations are selectively enriched in t-AML/t-MDS is unknown. Here, by sequencing the genomes of 22 patients with t-AML, we show that the total number of somatic single-nucleotide variants and the percentage of chemotherapy-related transversions are similar in t-AML and de novo AML, indicating that previous chemotherapy does not induce genome-wide DNA damage. We identified four cases of t-AML/t-MDS in which the exact TP53 mutation found at diagnosis was also present at low frequencies (0.003-0.7%) in mobilized blood leukocytes or bone marrow 3-6 years before the development of t-AML/t-MDS, including two cases in which the relevant TP53 mutation was detected before any chemotherapy. Moreover, functional TP53 mutations were identified in small populations of peripheral blood cells of healthy chemotherapy-naive elderly individuals. Finally, in mouse bone marrow chimaeras containing both wild-type and Tp53(+/-) haematopoietic stem/progenitor cells (HSPCs), the Tp53(+/-) HSPCs preferentially expanded after exposure to chemotherapy. These data suggest that cytotoxic therapy does not directly induce TP53 mutations. Rather, they support a model in which rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. The early acquisition of TP53 mutations in the founding HSPC clone probably contributes to the frequent cytogenetic abnormalities and poor responses to chemotherapy that are typical of patients with t-AML/t-MDS.

Alter BP
Fanconi anemia and the development of leukemia.
Best Pract Res Clin Haematol. 2014 Sep-Dec; 27(3-4):214-21 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 genes, whose protein products collaborate in a DNA repair pathway. The major complications are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. A severe subset, due to mutations in FANCD1/BRCA2, has a cumulative incidence of cancer of 97% by age 7 years; the cancers are AML, brain tumors, and Wilms tumor; several patients have multiple events. Patients with the other genotypes (FANCA through FANCQ) have cumulative risks of more than 50% of marrow failure, 20% of AML, and 30% of solid tumors (usually head and neck or gynecologic squamous cell carcinoma), by age 40, and they too are at risk of multiple adverse events. Hematopoietic stem cell transplant may cure AML and MDS, and preemptive transplant may be appropriate, but its use is a complicated decision.

Yasuda H, Takaku T, Tomomatsu J, et al.
Spontaneous regression of cutaneous blastic plasmacytoid dendritic cell neoplasm followed by acute monocytic leukemia evolving from myelodysplastic syndrome.
Intern Med. 2014; 53(23):2717-20 [PubMed] Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy arising from plasmacytoid dendritic cell precursors. BPDCN typically manifests in the skin, but it can also evolve into a leukemic form or be complicated by acute myeloid leukemia, some cases with a preceding myelodysplastic syndrome (MDS). We herein report the first case of complete spontaneous regression of cutaneous BPDCN followed by acute monocytic leukemia evolving from MDS. This is also the first reported case of gastric BPDCN invasion.

Smith C, Gasparetto M, Jordan C, et al.
The effects of alcohol and aldehyde dehydrogenases on disorders of hematopoiesis.
Adv Exp Med Biol. 2015; 815:349-59 [PubMed] Related Publications
Hematopoiesis involves the orderly production of millions of blood cells per second from a small number of essential bone marrow cells termed hematopoietic stem cells (HSCs). Ethanol suppresses normal hematopoiesis resulting in leukopenia, anemia, and thrombocytopenia and may also predispose to the development of diseases such as myelodysplasia (MDS) and acute leukemia. Currently the exact mechanisms by which ethanol perturbs hematopoiesis are unclear. The aldehyde dehydrogenase (ALDH) gene family plays a major role in the metabolism of reactive aldehydes derived from ethanol in the liver and other organs. At least one of the ALDH isoforms, ALDH1A1, is expressed at high levels in HSCs in humans, mice, and other organisms. Recent data indicate that ALDH1A1 and possibly other ALDH isoforms may metabolize reactive aldehydes in HSCs and other hematopoietic cells as they do in the liver and elsewhere. In addition, loss of these ALDHs leads to perturbation of a variety of cell processes that may predispose HSCs to disorders in growth and leukemic transformation. From these findings, we suggest a hypothesis that the cytopenias and possible increased risk of MDS and acute leukemia in heavy alcohol users is due to polymorphisms in genes responsible for metabolism of alcohol derived reactive aldehydes and repair of their DNA adducts in HSCs and other hematopoietic cells. In the article, we will summarize the biological properties of hematopoietic cells and diseases related to ethanol consumption, discuss molecular characteristics of ethanol metabolism, and describe a model to explain how ethanol derived reactive aldehydes may promote HSC damage.

Genovese G, Kähler AK, Handsaker RE, et al.
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
N Engl J Med. 2014; 371(26):2477-87 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
BACKGROUND: Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
METHODS: We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling.
RESULTS: Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones.
CONCLUSIONS: Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).

Jaiswal S, Fontanillas P, Flannick J, et al.
Age-related clonal hematopoiesis associated with adverse outcomes.
N Engl J Med. 2014; 371(26):2488-98 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
BACKGROUND: The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders.
METHODS: We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events.
RESULTS: Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8).
CONCLUSIONS: Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).

Dumitriu B, Feng X, Townsley DM, et al.
Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia.
Blood. 2015; 125(4):706-9 [PubMed] Article available free on PMC after 22/01/2016 Related Publications
The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs). Most patients respond to immunosuppressive therapies, but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (-7). Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of evolution to -7, and all had a dominant HSPC clone bearing specific acquired mutations. However, mutations in genes associated with MDS/AML were present in only 4 cases. Patients who evolved to MDS and AML showed marked progressive telomere attrition before the emergence of -7. Single telomere length analysis confirmed accumulation of short telomere fragments of individual chromosomes. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML after SAA, and provides a possible mechanism for development of aneuploidy.

Tang G, DiNardo C, Zhang L, et al.
MLL gene amplification in acute myeloid leukemia and myelodysplastic syndromes is associated with characteristic clinicopathological findings and TP53 gene mutation.
Hum Pathol. 2015; 46(1):65-73 [PubMed] Related Publications
MLL gene rearrangements are well-recognized aberrations in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In contrast, MLL gene amplification in AML/MDS remains poorly characterized. Here, we report a series of 21 patients with myeloid neoplasms associated with MLL gene amplification from 1 institution. This series included 13 men and 8 women, with a median age of 64 years. Eleven patients presented as AML with myelodysplasia-related changes, 6 as therapy-related AML, and 4 as therapy-related MDS. All patients had a highly complex karyotype, including frequent -5/del(5q), -18, and -17/del(17p) abnormalities; 16 patients were hypodiploid. TP53 mutations were detected in all 12 patients tested, and 3 patients showed TP53 mutation before MLL amplification. Morphologically, the leukemic cells frequently showed cytoplasmic vacuoles, bilobed nuclei, and were associated with background dyspoiesis. Immunophenotypically, 15 patients had a myeloid and 4 had myelomonocytic immunophenotype. Laboratory coagulopathies were common; 7 patients developed disseminated intravascular coagulopathy, and 3 died of intracranial bleeding. All patients were refractory to therapy; the median overall survival was 1 month, after MLL gene amplification was detected. We concluded that AML/MDS with MLL gene amplification is likely a subset of therapy-related AML/MDS or AML with myelodysplasia-related changes, associated with distinct clinicopathological features, frequent disseminated intravascular coagulopathy, a highly complex karyotype, TP53 deletion/mutation, and an aggressive clinical course.

Kinney AY, Butler KM, Schwartz MD, et al.
Expanding access to BRCA1/2 genetic counseling with telephone delivery: a cluster randomized trial.
J Natl Cancer Inst. 2014; 106(12) [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: The growing demand for cancer genetic services underscores the need to consider approaches that enhance access and efficiency of genetic counseling. Telephone delivery of cancer genetic services may improve access to these services for individuals experiencing geographic (rural areas) and structural (travel time, transportation, childcare) barriers to access.
METHODS: This cluster-randomized clinical trial used population-based sampling of women at risk for BRCA1/2 mutations to compare telephone and in-person counseling for: 1) equivalency of testing uptake and 2) noninferiority of changes in psychosocial measures. Women 25 to 74 years of age with personal or family histories of breast or ovarian cancer and who were able to travel to one of 14 outreach clinics were invited to participate. Randomization was by family. Assessments were conducted at baseline one week after pretest and post-test counseling and at six months. Of the 988 women randomly assigned, 901 completed a follow-up assessment. Cluster bootstrap methods were used to estimate the 95% confidence interval (CI) for the difference between test uptake proportions, using a 10% equivalency margin. Differences in psychosocial outcomes for determining noninferiority were estimated using linear models together with one-sided 97.5% bootstrap CIs.
RESULTS: Uptake of BRCA1/2 testing was lower following telephone (21.8%) than in-person counseling (31.8%, difference = 10.2%, 95% CI = 3.9% to 16.3%; after imputation of missing data: difference = 9.2%, 95% CI = -0.1% to 24.6%). Telephone counseling fulfilled the criteria for noninferiority to in-person counseling for all measures.
CONCLUSIONS: BRCA1/2 telephone counseling, although leading to lower testing uptake, appears to be safe and as effective as in-person counseling with regard to minimizing adverse psychological reactions, promoting informed decision making, and delivering patient-centered communication for both rural and urban women.

Xie M, Lu C, Wang J, et al.
Age-related mutations associated with clonal hematopoietic expansion and malignancies.
Nat Med. 2014; 20(12):1472-8 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

Lund K, Cole JJ, VanderKraats ND, et al.
DNMT inhibitors reverse a specific signature of aberrant promoter DNA methylation and associated gene silencing in AML.
Genome Biol. 2014; 15(8):406 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are neoplastic disorders of hematopoietic stem cells. DNA methyltransferase inhibitors, 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), benefit some MDS/AML patients. However, the role of DNA methyltransferase inhibitor-induced DNA hypomethylation in regulation of gene expression in AML is unclear.
RESULTS: We compared the effects of 5-azacytidine on DNA methylation and gene expression using whole-genome single-nucleotide bisulfite-sequencing and RNA-sequencing in OCI-AML3 cells. For data analysis, we used an approach recently developed for discovery of differential patterns of DNA methylation associated with changes in gene expression, that is tailored to single-nucleotide bisulfite-sequencing data (Washington University Interpolated Methylation Signatures). Using this approach, we find that a subset of genes upregulated by 5-azacytidine are characterized by 5-azacytidine-induced signature methylation loss flanking the transcription start site. Many of these genes show increased methylation and decreased expression in OCI-AML3 cells compared to normal hematopoietic stem and progenitor cells. Moreover, these genes are preferentially upregulated by decitabine in human primary AML blasts, and control cell proliferation, death, and development.
CONCLUSIONS: Our approach identifies a set of genes whose methylation and silencing in AML is reversed by DNA methyltransferase inhibitors. These genes are good candidates for direct regulation by DNA methyltransferase inhibitors, and their reactivation by DNA methyltransferase inhibitors may contribute to therapeutic activity.

Perry AM, Attar EC
New insights in AML biology from genomic analysis.
Semin Hematol. 2014; 51(4):282-97 [PubMed] Related Publications
Advancements in sequencing techniques have led to the discovery of numerous genes not previously implicated in acute myeloid leukemia (AML) biology. Further in vivo studies are necessary to discern the biological impact of these mutations. Murine models, the most commonly used in vivo system, provide a physiologic context for the study of specific genes. These systems have provided deep insights into the role of genetic translocations, mutations, and dysregulated gene expression on leukemia pathogenesis. This review focuses on the phenotype of newly identified genes, including NPM1, IDH1/2, TET2, MLL, DNMT3A, EZH2, EED, and ASXL1, in mouse models and the implications on AML biology.

Inoue D, Kitaura J, Matsui H, et al.
SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.
Leukemia. 2015; 29(4):847-57 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-β signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.

Lebel A, Yacobovich J, Krasnov T, et al.
Genetic analysis and clinical picture of severe congenital neutropenia in Israel.
Pediatr Blood Cancer. 2015; 62(1):103-8 [PubMed] Related Publications
BACKGROUND: The relative frequency of mutated genes among patients with severe congenital neutropenia (SCN) may differ between various ethnic groups. To date, few population-based genetic studies have been reported. This study describes the genetic analysis of 32 Israeli patients with SCN.
PROCEDURES: Clinical data were retrieved from the prospective Israeli Inherited Bone Marrow Failure Registry. Recruitment included living and deceased patients who were diagnosed between 1982 and 2012, for whom molecular diagnosis was performed. ELANE, HAX1 and G6PC3 genes were sequenced in all patients, and GFI-1 and WAS genes were sequenced if other genes were wildtype.
RESULTS: Eleven patients (34%) had heterozygous mutations in ELANE (10 kindreds), eight (25%) had homozygous mutations in G6PC3 (5 kindreds) and 13 (41%) had no detected mutations. No patients had mutations in HAX1 or WAS. Four of the eight patients with G6PC3 mutations had congenital anomalies. The probability of survival for all patients was 50% at age of 18. Deaths were mainly due to sepsis (5 patients, 4/5 not responding to G-CSF, none with G6PC3 mutation). Two patients developed acute myelogenous leukemia (AML) and one myelodysplastic syndrome (MDS), none with G6PC3 mutation.
CONCLUSIONS: We found a unique pattern of SCN mutations in Israel with homozygous G6PC3 mutations in eight (25%) patients, the highest frequency described so far. HAX1 mutations, reported mainly in Sweden and Iran, were absent. Patients with G6PC3 mutations had congenital anomalies, appeared to have a better response to G-CSF, and so far have not developed AML or MDS.

Srivastava P, Paluch BE, Matsuzaki J, et al.
Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts.
Leuk Res. 2014; 38(11):1332-41 [PubMed] Related Publications
The mechanism of clinical action for the FDA approved hypomethylating drugs azacitidine and decitabine remains unresolved and in this context the potential immunomodulatory effect of these agents on leukemic cells is an area of active investigation. Induced expression of methylated Cancer Testis Antigen (CTA) genes has been demonstrated in leukemic cell lines following exposure to hypomethylating drugs in vitro. SGI-110 is a novel hypomethylating dinucleotide with prolonged in vivo exposure and clinical activity in patients with MDS and AML. We demonstrate that this agent, like decitabine, produces robust re-expression of the CTAs NY-ESO-1 and MAGE-A, both in vitro and in leukemia-bearing AML xenografts. Upregulation of these genes in vitro was sufficient to induce cytotoxicity by HLA-compatible CD8+ T-cells specific for NY-ESO-1, a well-recognized and immunogenic CTA. Additionally, exposure to SGI-110 enhances MHC class I and co-stimulatory molecule expression, potentially contributing to recognition of CTAs. SGI-110, like the parent compound decitabine, induces expression of CTAs and might modulate immune recognition of myeloid malignancy.

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