Next-Generation Sequencing Technology Reveals a Characteristic Pattern of Molecular Mutations in 72.8% of Chronic Myelomonocytic Leukemia by Detecting Frequent Alterations in TET2, CBL, RAS, and RUNX1

Kohlmann, Alexander; Großmann, Vera; Klein, Hans-Ulrich; Schindela, Sonja; Weiss, Tamara; Kazak, Beray; Dicker, Frank; Schnittger, Susanne; Dugas, Martin; Kern, Wolfgang; Haferlach, Claudia; Haferlach, Torsten

doi:10.1200/jco.2009.27.1361

Cited by 276 publications

(261 citation statements)

References 29 publications

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“…29,30 Although TET2 mutations can represent early molecular events in myeloproliferative neoplasms, in a recent study of JAK2 mutation-positive myeloproliferative neoplasms based on colony assays, genotyping for TET2 and JAK2 mutations, it was demonstrated that TET2 can be a late event in the progression of myeloproliferative neoplasms and may represent an acquired abnormality in a separate (JAK2 mutation-negative) clone. 31 It is intriguing to speculate that the acquisition of KRAS, TET2 or other mutagenic events could have played a role in the phenotypic shift observed in our cases. One could hypothesize that possibly either owing to clonal defect present at the disease onset in only a minority of the cells and its subsequent expansion, or because of a new genetic event acquired later in the course of the disease, some patients with myeloproliferative neoplasms have a monocytic proliferation capacity that eventually manifests as a chronic myelomonocytic leukemia or chronic myelomonocytic leukemia-like phenotype.…”

Section: Discussionmentioning

confidence: 84%

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

et al. 2013

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Primary myelofibrosis is a type of chronic myeloproliferative neoplasm characterized by progressive bone marrow failure with worsening cytopenia and in a subset of patients, progression to acute leukemia. Published data in patients with myelodysplastic syndromes have shown that the development of monocytosis in the course of myelodysplastic syndromes is associated with a poor prognosis. A similar occurrence has been only sporadically reported in patients with primary myelofibrosis. Over a period of four years we identified 10 out of 237 cases of primary myelofibrosis who developed persistent absolute monocytosis (41 Â 10 9 /l) during the course of disease (5 men and 5 women; median age/range: 68 years/52-82). Monocytosis developed at a median interval of 42 months from diagnosis (range: 1-180) and persisted for a median period of 23 months (range: 2-57). Five patients died after developing monocytosis (range: 20-188 months) and two experienced worsening disease and became transfusion dependent. Monocytosis was associated with increased white blood cells, decreased hemoglobin, decreased platelet count, and the presence of circulating blasts. In three cases, bone marrow biopsies after the onset of monocytosis showed marked myelomonocytic proliferation with morphological shifting from a typical primary myelofibrosis marrow appearance to aspects compatible with an overt 'secondary' chronic myelomonocytic leukemia. Before the development of monocytosis, 5 of 10 patients carried the JAK2V617F mutation; five patients showed karyotypic alterations. No change in JAK2 mutational status or cytogenetic evolution were associated with the development of monocytosis. Four of nine patients analyzed showed KRAS mutation in codon 12 or 13 with low allele burden. This is the first study correlating monocytosis developing in primary myelofibrosis patients with bone marrow morphology, laboratory data, molecular analysis and clinical follow-up. Development of monocytosis in patients with established primary myelofibrosis is associated with rapid disease progression and these patients should be considered as a high-risk group associated with short survival.

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Section: Discussionmentioning

confidence: 84%

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

et al. 2013

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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%

“…research article transcription factors such as JAK2, KRAS, NRAS, and RUNX1 [26,29]. Thus far, in CMML loss of function gene mutations involving ASXL1 and EZH2 have been associated with poor outcome [10,11].…”

Section: Discussionmentioning

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

136

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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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“…responsible for its repression during MK differentiation, which may explain the presence of low ploidy MK in runx1 f/f(Mx1 Cre + ) mice 24,25 , as well as in hereditary or acquired haematological disorders associated with RUNX1 loss-of-function mutations 35,36 . Low-ploidy MK has been observed in KO of other transcription factors, such as GATA1 or FLI-1 (refs 37,38).…”

Section: Discussionmentioning

confidence: 99%

RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization

et al. 2012

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megakaryocytes are unique mammalian cells that undergo polyploidization (endomitosis) during differentiation, leading to an increase in cell size and protein production that precedes platelet production. Recent evidence demonstrates that endomitosis is a consequence of a late failure in cytokinesis associated with a contractile ring defect. Here we show that the non-muscle myosin IIB heavy chain (mYH10) is expressed in immature megakaryocytes and specifically localizes in the contractile ring. mYH10 downmodulation by short hairpin RnA increases polyploidization by inhibiting the return of 4n cells to 2n, but other regulators, such as of the G1/s transition, might regulate further polyploidization of the 4n cells. Conversely, re-expression of mYH10 in the megakaryocytes prevents polyploidization and the transition of 2n to 4n cells. During polyploidization, mYH10 expression is repressed by the major megakaryocyte transcription factor RunX1. Thus, RunX1-mediated silencing of mYH10 is required for the switch from mitosis to endomitosis, linking polyploidization with megakaryocyte differentiation.

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Next-Generation Sequencing Technology Reveals a Characteristic Pattern of Molecular Mutations in 72.8% of Chronic Myelomonocytic Leukemia by Detecting Frequent Alterations in TET2, CBL, RAS, and RUNX1

Cited by 276 publications

References 29 publications

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

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

RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization

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