Myelomonocytic skewing in chronic myelomonocytic leukemia: phenotypic, molecular and biologic features and impact on survival

Abstract

Background Myelomonocytic skewing is considered as a key pathophysiologic phenomenon in chronic myelomonocytic leukemia (CMML), but its prevalence and potential correlation with phenotypic, genotypic, and clinical features are poorly defined. Methods Skewed differentiation toward the myelomonocytic over erythroid commitment as indicated by an inverse ratio of myelomonocytic/erythroid colonies was investigated in 146 patients with CMML by semisolid in vitro cultures. Results There was a high prevalence of myelomonocytic skewing in patients with CMML (120/146, 82%); whereas, this phenomenon was rare in normal individuals (1/98, 1%). Patients with CMML with myelomonocytic skewing had higher white blood cell and peripheral blast cell counts, and lower platelet values. The number of mutations in genes of the epigenetic and/or splicing category was higher in CMML patients with as compared with patients without skewing. Patients with myelomonocytic skewing had more frequently mutations in RASopathy genes and higher growth factor independent myeloid colony formation. Interestingly, the lack of myelomonocytic skewing discriminated patients with CMML with a particularly favorable prognosis (60 vs 19 months, P = .003) and a minimal risk of transformation. Conclusion Myelomonocytic skewing as determined by semisolid cultures can discriminate subgroups of patients with CMML with a different phenotype, a different genotype, and a different prognosis.

Multistep pathogenesis of chronic myelomonocytic leukemia in patients

“…Median values and ranges of CFU‐GM/10 5 MNC were 0.5 (0–3), 3 (0–35), and 59 (3–202), in T, TS, and TSN, respectively (Table ). Myelomonocytic skewing is another important in vitro characteristic in CMML and is indicated by a higher number of myeloid over erythroid colonies from PBMNC 14,15 . As we have reported previously, there was a high prevalence of myelomonocytic skewing in CMML patients (120/146, 82%), whereas this phenomenon was rare in normal individuals (1/98, 1%) 15 .…”

“…[10][11][12] The biologic basis for this observation was provided by Padron et al when he reported hypersensitivity of CMML progenitors using phospho-STAT5 flow cytometry. 26 Moreover, our group could show in a small retrospective study that CMML patients with high spontaneous CFU-GM growth (>100/10 15 In this study, we found that myelomonocytic skewing was not observed in the CMML patients with a TET2 mutation alone, but was seen in more than half of the patients who had only a TET2/SRSF2 mutation and in all patients who had additional NRAS mutations. This indicates that the preferential expansion of myelomonocytopoiesis over erythropoiesis in CMML is a biologic phenomenon starting at the CMML stage characterized by the comutation of genes of the epigenetic and the spliceosome regulation and further parallels the progression of CMML into more advanced disease.…”

Molecular Pathogenesis of Chronic Myelomonocytic Leukemia and Potential Molecular Targets for Treatment Approaches

“…Semisolid in vitro cultures from PBMNC of normal individuals usually contain a higher concentration of erythroid colonies (BFU-E) as compared to myeloid colonies (CFU-GM). Skewed differentiation toward the myelomonocytic over erythroid commitment in patients, as indicated by an inverse BFU-E/CFU-GM ratio, is a common finding in CMML patients ( 39 ). Interestingly, the lack of myelomonocytic skewing separated patients with a particularly favorable prognosis and a minimal risk of transformation.…”

“…Geissler et al. could demonstrate that myelomonocytic skewing as determined by semisolid cultures can separate subgroups of CMML patients with a different phenotype, a different genotype and a different prognosis ( 39 ). The definitive link of this phenomenon to the pathophysiology of CMML comes from animal studies in which hematopoietic cells are genetically manipulated with molecular aberrations that are commonly found in CMML patients.…”

“…Moreover, in juvenile myelomonocytic leukemia (JMML) in which molecular aberrations are mainly restricted to RASopathy genes autonomous myeloid colony formation due to GM-CSF-specific hypersensitivity is a hallmark feature of disease, which has been included in the diagnostic criteria (80). In a small series of CMML patients who had in vitro cultures and molecular analyses Geissler et al observed a close correlation between high spontaneous myeloid colony growth and the presence (39). The definitive link of this phenomenon to the pathophysiology of CMML comes from animal studies in which hematopoietic cells are genetically manipulated with molecular aberrations that are commonly found in CMML patients.…”