Chronic myelomonocytic leukemia patients with RAS pathway mutations show high in vitro myeloid colony formation in the absence of exogenous growth factors

Geißler, Klaus; Jäger, Eva; Barna, Agnes; Alendar, Temeida; Ljubuncic, Elmir; Sliwa, Thamer; Valent, Peter

doi:10.1038/leu.2016.235

Cited by 25 publications

(23 citation statements)

References 8 publications

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“…87,88 Therapeutic approaches targeting this signaling pathway are currently being assessed, 89 including the use of ruxolitinib that could control inflammatory symptoms (Table 3). 90 Extramedullary disease MPN-CMML patients can experience constitutional symptoms, including fatigue, diffuse bone pain, and night sweats, and develop a splenomegaly (;30% of cases), which is occasionally troublesome, resulting from extramedullary hematopoiesis.…”

Section: Myeloproliferative Cmmlmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

101

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 109/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 109/L) and proliferative (white blood cell count ≥13 × 109/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient’s quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.

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Section: Myeloproliferative Cmmlmentioning

confidence: 99%

How I treat chronic myelomonocytic leukemia

Solary

Itzykson

2017

Blood

101

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“…In preclinical mouse models, molecular alterations of RASopathy genes in murine hematopoietic cells are leading to a myelomonocytic leukemia like phenotype in vivo and to spontaneous myeloid colony formation due to GM-CSF hypersensitivity in vitro [21][22][23][24][25]. Recently we were able to demonstrate a close correlation between increased spontaneous colony formation in CMML patients and the presence of RAS-pathway mutations [26]. Together these findings strongly suggest that high spontaneous in vitro CFU-GM formation in CMML reflect RAS-pathway hyperactivation at a functional level.…”

Section: Introductionmentioning

confidence: 98%

Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients

Geißler

Jäger

Barna

et al. 2020

IJMS

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Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.

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“…Historically, the first identified, notably by colony assays [41] and phospho-flow cytometry [42] is hypersensitivity of myeloid progenitors to GM-CSF signaling, with increased phospho-STAT5 activity as a critical transducer of this phenotype. However, recent studies have stressed that this mechanism is not universal and in fact appears restricted to the 35-50% of CMML cases that harbor somatic mutations in cytokine signaling pathway [43][44][45]. These cases partly, but not fully, correspond to MP-CMML.…”

Section: Molecular Lesions and Pathogenesismentioning

confidence: 99%