JAK2<sup>V617F</sup>activating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia

Pich, Achille; Riera, Ludovica; Sismondi, Francesca; Godio, Laura; Bonino, Laura Davico; Marmont, Filippo; Celle, Paola Francia di

doi:10.1136/jcp.2009.065904

Cited by 45 publications

(26 citation statements)

References 16 publications

(17 reference statements)

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“…22 A similar effect has been reported for the occurrence of an acquired JAK2 mutation in patients with chronic myelomonocytic leukemia. 23 However, in contrast to chronic myelomonocytic leukemia, no evidence of RAS or FLT3 mutations were found in cases of myelodysplastic syndromes with secondary 'monocytic evolution'. 6 In our series, a KRAS mutation in exons 12 or 13 was detected in 4/9 cases at some point, including the two patients with chronic myelomonocytic leukemia-like marrow appearance.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2013

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“…In particular, although RAS mutations seem to be the most commonly identified genetic aberration in MP-CMML, the FLT3-ITD (28) and the JAK2 V617F substitution (29,30) have also been found in a minority of patients. Indeed, we detected the FLT3-ITD in a case of MD-CMML who rapidly progressed to MP-CMML and then to acute leukemia (patient 31) and the JAK2 V617F substitution in two cases classified as MP-CMML at the time of first presentation (patients 23 and 35; results not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Other genetic defects (i.e., FLT3-ITD and JAK2 V617F substitution; refs. [28][29][30] have been identified at a higher frequency among MP-CMML than MD-CMML patients, in a manner mutually exclusive with RAS mutations, and have been shown to induce a chronic myelomonocytic leukemialike disease in mice (i.e., the FLT3-ITD and BID deletion; refs. 28,31), implying a role in the establishment of myeloproliferation.…”

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confidence: 99%

RAS Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

Ricci

Fermo

Corti

et al. 2010

Clinical Cancer Research

124

103

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Purpose: The biological and clinical heterogeneity of chronic myelomonocytic leukemia features renders its classification difficult. Moreover, because of the limited knowledge of the mechanisms involved in malignant evolution, chronic myelomonocytic leukemia remains a diagnostic and therapeutic challenge and a poor prognosis disease. We aimed to verify the biological and clinical significance of the discrimination, based on the leukocyte count, between myelodysplastic chronic myelomonocytic leukemia (MD-CMML) and myeloproliferative chronic myelomonocytic leukemia (MP-CMML).Experimental Design: Peripheral blood samples from 22 patients classified as MD-CMML and 18 as MP-CMML were collected at different time points during disease course, and patients' clinical characteristics were examined. RAS mutational screening was done by sequencing and, for each substitution identified, a highly selective allele-specific PCR was set up to screen all specimens.Results: MP-CMML patients showed a significantly poorer survival (P = 0.003) and a higher frequency of RAS mutations (P = 0.033) by sequencing compared with MD-CMML. Overall, five MD-CMML patients progressed to myeloproliferative disease: in two, allele-specific PCR unveiled low levels of the RAS mutations predominating in the myeloproliferative phase at the time of myelodysplastic disease, documenting for the first time the expansion of a RAS mutated clone in concomitance with chronic myelomonocytic leukemia evolution. Moreover, one of the progressed patients harbored the FLT3-ITD and two MP-CMML patients presented with the JAK2 V617F substitution. All these lesions were mutually exclusive.Conclusions: Our results strongly suggest RAS mutations to function as a secondary event that contributes to development of the chronic myelomonocytic leukemia variant with the poorer prognosis (MP-CMML) and therefore advise their detection to be implemented in chronic myelomonocytic leukemia diagnostics and monitoring. Clin Cancer Res; 16(8); 2246-56. ©2010 AACR.

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“…Thus far, RAS pathway mutations (KRAS and NRAS), RUNX1 alterations, JAK2V617F point mutations, CBL, MPL mutations and TET2 alterations have been described. [8][9][10][11] Kohlmann et al 12 recently showed a characteristic pattern of molecular mutations in 72.8% of patients with CMML. In particular, TET2, CBL and RAS pathway alterations were detected, leading to a more precise molecular classification in CMML.…”

Section: Introductionmentioning

confidence: 99%

Current status of allogeneic HST for chronic myelomonocytic leukemia

Cheng

Kirtani

Gergis

2011

Bone Marrow Transplant

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JAK2^V617Factivating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia

Cited by 45 publications

References 16 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

RAS Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

Current status of allogeneic HST for chronic myelomonocytic leukemia

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JAK2V617Factivating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia

Cited by 45 publications

References 16 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

RAS Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant

Current status of allogeneic HST for chronic myelomonocytic leukemia

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JAK2^V617Factivating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia