Myeloproliferative neoplasm pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

Overview

Clinical and pathologic features in the myeloproliferative neoplasms are due to dysregulated proliferation and expansion of myeloid progenitors in the bone marrow, resulting in altered populations of granulocytes, erythrocytes, or platelets in the peripheral blood.

Genetics

Primary cytogenetic abnormalities have not been identified in the majority of myeloproliferative neoplasms. Aberrant activation of tyrosine kinases and associated signaling pathways is frequently implicated as the disease-initiating event.

Chronic Myelogenous Leukemia

In Philadelphia chromosome translocation, parts of two chromosomes (the 9^th and 22^nd by conventional karyotypic numbering) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p is a weight measure of cellular proteins in kDa). Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the BCR-ABL fusion gene product is also a tyrosine kinase. The fused BCR-ABL protein interacts with the interleukin 3beta c receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn BCR-ABL activates a cascade of proteins which control the cell cycle, speeding up cell division. Moreover the bcr-abl protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia.

Polycythemia Vera

• Gene involved in the pathogenesis of polycythemia vera is Janus kinase 2 (JAK2 kinase) will lead to activation of the following pathways:

• JAK-STAT
• PI3K (phosphoinositide-3-kinase)
• AKT (protein kinase B)

• The activation of these pathways causes neoplastic proliferation and maturation of erythroid cells.

Essential Thrombocythemia

Calreticulin gene (CALR) gene involved in the pathogenesis of essential thrombocythemia.

Primary Myelofibrosis

Genes involved in the pathogenesis of primary myelofibrosis include Janus kinase 2 (JAK2 kinase) and Calreticulin (CALR). Primary myelofibrosis is hallmarked by clonal myeloproliferation with reactive stromal changes in response to uncontrolled production of growth factors (e.g., transforming growth factor β, platelet-derived growth factor, and basic fibroblast growth factor) from resident megakaryocytes and monocytes. The etiopathogenic mutations leading to primary myelofibrosis remain unclear.

Gallery

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  Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.

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  Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell