Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A

Jankowska, Anna; Makishima, Hideki; Tiu, Ramon V.; Szpurka, Hadrian; Huang, Yun; Traina, Fabı́ola; Visconte, Valeria; Sugimoto, Yuka; Prince, Courtney; O’Keefe, Christine L.; Hsi, Eric D.; List, Alan F.; Sekeres, Mikkael A.; Rao, Anjana; McDevitt, Michael A.; Maciejewski, Jaroslaw P.

doi:10.1182/blood-2010-10-311019

Cited by 298 publications

(241 citation statements)

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“…A gain-of-function mutation for EZH2 has been described in large cell lymphoma (28). On the other hand, heterozygous and homozygous mutation and/or deletion of EZH2 has been described in some hematologic malignancies (8)(9)(10)(11)(12)29), but is not typically seen in AML. Understanding of PRC2 biology in cancer is limited by the heterogeneity of clinical samples and the pleiotropy of genetic programs controlled by PRC2.…”

Section: Discussionmentioning

confidence: 99%

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Neff

Sinha

Kluk

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

202

218

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A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML. epigenetics | mouse model | polycomb group proteins | myeloid-lymphoid leukemia protein P olycomb repressive complex 2 (PRC2) has been implicated in development and cancer (1, 2). PRC2 is composed of the core components embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and a SET-domain methyltransferase, either enhancer of zeste 2 (EZH2) or enhancer of zeste 1 (EZH1) (3). The PRC2 complex catalyzes the di-and trimethylation of lysine residue 27 of histone 3 (H3K27me3), a repressive chromatin mark (4). Overexpression of EZH2 has been correlated with prostate cancer progression (5). Follow-up studies have confirmed and expanded these results for other cancer types, mainly solid tumors. In the hematopoietic system, forced expression of Ezh2 increases serial transplantation potential in hematopoietic stem cells (6) and enhances transformation in a model of multiple myeloma (7). Intriguingly, heterozygous loss of function of EZH2 has been associated with adverse prognosis in myelofibrosis (8), and heterozygous and homozygous inactivation of EZH2 has been described in myelodysplastic syndromes and more recently in Tlineage lymphoblastic leukemia (9-12). In contrast, EZH2 alterations appear to be rare events in acute myeloid leukemia (AML). How to reconcile these findings on a mechanistic level is unclear. Given the heterogeneity of clinical samples, elucidating the complex role of PRC2 biology in cancer will be aided by studies in genetically defined animal models (13).Loss of function of PRC2 has been evaluated in several cancer models (14, 15). However, shRNA...

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Section: Discussionmentioning

confidence: 99%

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Neff

Sinha

Kluk

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

202

218

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“…The advent of next generation sequencing technology has led to the identification of molecular aberrations in 90% of patients with CMML [9,14,26]. These can broadly be divided into four categories: mutations involving epigenetic regulator genes such as EZH2, ASXL1, TET2, DNMT3A, IDH1, and IDH2 [9,10,14,27], mutations involving the spliceosome machinery such as SF3B1, SRSF2, U2AF35, ZRSR2, SF3A1, PRPF40B, U2AF65, and SF1 [13,14,19,20], mutations involving DNA damage response genes such as Tp53 [28], and mutations involving genes regulating cellular/receptor tyrosine kinases and (13) 12 (100) 9 (75) 3 (25) delP95R-R102-7 (8) 7 (100) 3 (43) 1 (14) R94-P95insR-1 (1) 1 ( (25) 5 (100) 5 (100) 0 (0) Q157G-1 (5) 0 (0) 0 (0) 1 (100) R158H-1 (5) 1 (100) 1 (100) 0 (0) CMML-1, chronic myelomonocytic leukemia-1; SF3B1, splicing factor 3B, subunit 1; SRSF2, serine/arginine-rich splicing factor 2; U2AF35, U2 small nuclear RNA auxiliary factor 1.…”

Section: Discussionmentioning

confidence: 99%

“…These include mutations involving; RUNX1 [3], IDH1, and IDH2 [4], KRAS and NRAS [5], CBL [6], JAK2 [7], TET2 [8], DNMT3A [9], ASXL1 [10], UTX [9], and EZH2 [9]. Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11].…”

Section: Introductionmentioning

confidence: 99%

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Patnaik¹,

Lasho²,

Finke³

et al. 2013

American J Hematol

141

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SRSF2, SF3B1, and U2AF35 (U2AF1) are the three most frequent genes involved with spliceosome mutations in myeloid malignancies. SF3B1 mutations are most frequent (~80%) in myelodysplastic syndromes (MDS) with ring sideroblasts (RS) but lack prognostic relevance. SRSF2 mutations are associated with shortened overall (OS) and leukemia-free survival (LFS) in both MDS and myelofibrosis. In this study of 226 patients with chronic myelomonocytic leukemia (CMML), mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35 (mostly S34F and Q157P/R). These mutations were mutually exclusive and 54% of the patients displayed at least one mutation. The three mutation groups were phenotypically similar, with the exception of higher RS% (P < 0.0001) in patients with SF3B1 mutations. At a median follow-up of 15 months, 176 (78%) deaths and 32 (14%) leukemic transformations were documented. OS (median survivals of 17, 16, 17, and 20 months; P 5 0.48) and LFS (leukemic transformation rates of 17, 13, 15, and 5%; P 5 0.63) were similar among patients with none of the three mutations, SRSF2, SF3B1, or U2AF35 mutations, respectively. We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant. Am. J. Hematol. 88:201-206, 2013. V C 2012 Wiley Periodicals, Inc. IntroductionChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by features overlapping between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The 2008 World Health Organization (WHO) criteria for diagnosis of CMML include; persistent peripheral blood monocytosis >1 3 10(9)/L, absence of the BCR-ABL1 fusion, absence of rearrangements of the PDGFRA or PDGFRB genes, absence of 20% myeloblasts or promonocytes in the blood and bone marrow (BM), and presence of dysplasia in one or more myeloid lineages [1]. CMML is further subclassified into CMML-1 (<5% circulating blasts and <10% BM blasts) and CMML-2 (5-19% circulating blasts, 10-19% BM blasts, or when Auer rods are present irrespective of the blast count), with the median over-all survival (OS) being 20 and 15 months respectively [1,2].Genetic aberrations are common in CMML and tend to involve different cellular targets and epigenetic regulatory pathways. These include mutations involving; RUNX1 . Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.Mutations in genes of the splicing machinery, such as SF3B1 (splicing factor 3B, subunit 1), SRSF2 (serine/arginine-rich splicing factor 2) and U2AF35, also known as U2AF1 (U2 small nuclear RNA auxiliary factor) are common in patients with myeloid malignancies [12][13][14]. SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16]. Similarly, these...

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“…Based on the DNA sequencing, several somatic gene mutations in patients with CML-BC has been revealed. These gene including RUNX1, ASXL1, IKZF1, WT1, TET2, IDH1, IDH2, NRAS, KRAS, CBL, CBLB, TP53, and GATA2 (Zhang et al, 2008;Grossmann et al, 2011;Makishima et al, 2011).…”

Section: Dear Editormentioning

confidence: 99%

“…Mutations in the EZH2 gene were recently described in patients with B-cell lymphomas (Morin et al, 2010), chronic myelomonocytic leukemia (CMML) ( Jankowska et al, 2011), adult and pediatric acute myeloid leukemia (Makishima et al, 2010;Ernst et al, 2012), myelofibrosis (Guglielmelli et al, 2011), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (Ernst et al, 2010;Makishima et al, 2010). It was revealed that EZH2 mutations were correlated with poor survival.…”

Section: Dear Editormentioning

confidence: 99%