Current insights in the cellular and molecular biology of chronic myelomonocytic leukemia

Abstract

SUMMARY Chronic myelomonocytic leukemia is a rare clonal myeloid disorder most often seen in the elderly that remains a virtually incurable disease. Chronic myelomonocytic leukemia has long been considered as a myelodysplastic syndrome by diagnostic classifications, but recent insights in the cellular and molecular biology of the disease has refined its identity. The malignant clone was shown to generate myeloid-derived suppressive cells that may contribute to disease expansion, whereas the role of progenitor hypersensitivity to granulomonocyte colony-stimulating factor probably defines two distinct subgroups. At least one gene mutation can now be identified in almost all the patients. The most frequently mutated genes are TET2, SRSF2 and ASXL1, with a frequent combination of mutations in the first two genes, whereas ASXL1 mutations define a poor prognostic subgroup of patients. A number of additional mutations have been identified that confer to the disease its phenotype specificity; for example, mutations in RUNX1 induce thrombocytopenia, those in SF3B1 can be associated with anemia, and those in signaling molecules including NRAS, KRAS, CBL, JAK2 and FLT3, characterize the proliferative forms of the disease. Based on these recent observations, new working models on disease pathogenesis are proposed and may serve as a basis for the search for alternative and more efficient therapeutic approaches.