cyclin-d1 and Thrombocytopenia

Platelets are produced from mature megakaryocytes which undergo polyploidization and proplatelet formation. Cell-cycle regulation plays a crucial role in megakaryocyte terminal differentiation especially in polyploidization. Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) controls cell-cycle progression in cancer cells. The objective of this study was to determine DYRK1B function in megakaryocyte maturation and platelet production. A DYRK1B knock-out mouse was generated with increased peripheral platelet count compared with the wild type mouse without affecting megakaryocyte numbers in bone marrow. Polyploidy and proplatelet formations were significantly enhanced when DYRK1B was depleted in vitro. DYRK1B inhibition promoted megakaryocyte maturation by simultaneously upregulating cyclin D1 and downregulating P27. Furthermore, there was platelet restoration in two mice disease models of transient thrombocytopenia. In summary, DYRK1B plays an important role in megakaryocyte maturation and platelet production by interacting with cyclin D1 and P27. DYRK1B inhibition has potential therapeutic value in transient thrombocytopenia treatment. Graphic Abstract.

Topics: Animals; Blood Platelets; Cyclin D1; Megakaryocytes; Mice; Phosphorylation; Thrombocytopenia; Tyrosine

Overlapping of essential thrombocythemia (ET) and multiple myeloma (MM) has been extremely rare. Our report concerns a case with concomitant ET and MM, where JAK2V617F was present in non-myeloma peripheral blood leukocytes and bone marrow (BM) hematopoietic cells, but not in BM-derived CD138-positive myeloma cells. In contrast, double-color fluorescence in situ hybridization analysis showed that BM-derived CD138-positive myeloma cells possessed the gene translocation between the immunoglobulin heavy chain gene and the cyclin D1 gene, which was not involved in non-myeloma hematopoietic cells. This is the first case with concomitant ET and MM in which the 2 hematologic neoplasms were shown to have originated from separate malignant clones at hierarchically different differentiation levels resulting from independent acquisition of different molecular aberrations. Among the 10 reported cases, including ours, ET preceded MM in 8 cases, but MM never preceded ET. We suggest that MM clones may have greater proliferative potency compared with ET clones, and that the treatment modification from ET to MM did not seem to exacerbate ET in most reported cases, perhaps because of the suppression of the ET clone by both the cytotoxic effect of anti-myeloma therapy and the clonal repression by MM progression.

Topics: Aged; Amino Acid Substitution; Cyclin D1; Female; Hematopoietic Stem Cells; Humans; Immunoglobulin Heavy Chains; Janus Kinase 2; Leukocytes; Multiple Myeloma; Mutation, Missense; Syndecan-1; Thrombocytopenia; Translocation, Genetic