Myeloproliferative neoplasm pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Genetics
The major clinical and pathologic findings in the chronic myeloproliferative disorders are due to dysregulated proliferation and expansion of myeloid progenitors in the bone marrow, resulting in increased numbers of mature granulocytes, red blood cells and/or platelets in the peripheral blood.Although no specific genetic abnormalities or disease-initiating events have yet been identified for most of the CMPDs, abnormal activation of tyrosine kinase-dependent signal transduction pathways are frequently implicated in their pathogenesis.
In CML, the phialdelphia (Ph) chromosome results in the formation of a hybrid gene, the BCR/ABL fusion gene, that includes regions of the ABL gene which encodes a nonreceptor tyrosine kinase important in signal translocation and regualtion of cell growth, translocated from chromosome 9 to chromosome 22, where they are juxtaposed with sequences of the BCR gene. Juxtaposition of ABL with sequences of BCR results in enhanced tyrosine kinase activity and constitutive overactivity of tyrosine phosphokinase. Haemotopoeitic cell lines transfected with BCR/ABL cDNA exhibit growth-factor independent proliferation in vitro and tumourogenicity in vivo and while deletion abrogates these transforming effects. In addition, the protein leads to increased transcription of MYC and BCL-2, which may protect the leukaemic cells from apoptosis. Therefore the expansion of the neoplastic clone may be due not only to increased proliferation but also to prolonged survival.
In PV, the erythroid progenitors are hypersensitive to a number of growth factors, including insulin-like growth factor-1 (IGF-1). The receptor for IGF-1, a member of the tyrosine kinase family of receptors, is hyperphosphorylated in the erythroid precursors in PV, and this could permit abnormal activation of a number of pathways such as RAS. In addition, as in CML, there is increased transcription of genes that block apoptosis in PV.Whether similar molecular events will be found in the other CMPDs remain to be seen.The events that lead to disease progression in any of the CMPDS are poorly understood at the current time.
One of the important bone marrow findings that overlaps the various CMPD entities is myelofibrosis. The fibrosis is most likely caused by the abnormal production and release of several cytokines and growth factors, such as platelet-derived growth factor and transforming growth factor-Beta (TFG-B), by megakaryocytes and other marrow cells. These cytokines stimulate fibroblastic proliferation and the synthesis of fibronectin and collagen.