Imatinib in treatment of thrombocythemia and other myeloproliferative diseases / 中国实验血液学杂志

Imatinib mesylate has been commonly used in the treatment of patients with chronic myeloid leukemia (CML). However, a significant number of CML patients treated with imatinib developed thrombocytopenia, oligocythemia, granulocytopenia. It has been confirmed that imatinib not only inhibits BCR-ABL mutations, but also suppresses other tyrosine kinase receptor genes such as PDGFR, JAK2V617F and C-KIT mutations, providing an important potential of targeted therapy for myeloproliferative disease. As the PDGFR, JAK2 and C-KIT play important roles in the regulation of hematopoiesis, suggesting that imatinib may block the phosphorylation of PDGFR, JAK2V617F and C-KIT receptors, interrupt the signal transduction cascades, disrupt cell differentiation and proliferation. In this review, the application and the potential molecular mechanism of imatinib in the treatment of thrombocythemia and other myeloproliferative diseases are discussed.

The role of PDGF/PDGFR in the regulation of platelet formation / 中国实验血液学杂志

Platelet-derived growth factor (PDGF), a potent chemotactic and mitogenic factor, is involved in the regulation of hematopoiesis and platelet production. Our studies demonstrate the presence of functional PDGF receptors (PDGFR) on human megakaryocytes/platelets and CD34(+) cells, and their ability to mediate a mitogenic response. PDGF promotes the ex vivo expansion of human hematopoietic stem (CD34(+)) and progenitor (CD41(+)) cells. More significantly, PDGF enhances the engraftment of human CD45(+) cells and their myeloid subsets (CD33(+), CD14(+) cells) in NOD/SCID mice. PDGF also stimulates in vitro megakaryocytopoiesis via PDGFR and/or the indirect effect on bone marrow microenvironment to produce TPO and other cytokines. It also shows a direct stimulatory effect of PDGF on c-Fos, GATA-1 and NF-E2 expressions in megakaryocytes. We speculate that these transcription factors may be involved in the signal transduction of PDGF on the regulation of megakaryocytopoiesis. PDGF also enhances platelet recovery in mouse model with radiation-induced thrombocytopenia. This radioprotective effect is likely to be mediated via PDGFR with subsequent activation of the PI3K/Akt pathway. It provides a possible explanation that blockage of PDGFR may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia.

Molecular mechanism of imatinib-induced thrombocytopenia in treatment of patients with CML / 中国实验血液学杂志

Imatinib mesylate has been commonly used in the treatment of patients with chronic myeloid leukemia (CML). However, a significant number of CML patients treated with imatinib developed thrombocytopenia. Platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) plays a significant role in the regulation of thrombopoiesis. It is suggested that imatinib may block the PDGF/PDGFR and PI3-K/Akt pathway, then inducing the apoptosis of megakaryocytes and developing thrombocytopenia in these patients. In this review, the potential molecular mechanism of imatinib-induced thrombocytopenia in the treatment of CML patients is discussed, including imatinib and thrombocytopenia, PDGF/PDGFR and thrombopoiesis, potential mechanism of imatinib-induced thrombocytopenia in treatment of patients with CML and so on.