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.

Pathophysiology

The pathophysiology of myeloproliferative neoplasms is based on the specific subtype of myeloproliferative neoplasm. 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.

Polycythemia Vera

In order to understand the pathophysiology of polycythemia vera, one must understand normal physiology of erythroid cell production. Under normal conditions, the hormone erythropoietin will bind to the erythropoietin receptor on erythroid cells, resulting in activation of the JAK-STAT signaling pathway. Specifically, the erythropoietin receptor is associated with the JAK2 protein, and binding of the erythropoietin receptor by its endogenous ligand (erythropoietin) will stimulate a basal level of erythroid cell production. In patients with polycythemia vera, this normal signaling process is excessively activated and dysregulated. The pathophysiology of polycythemia vera is well-defined and is specific to this subcategory of myeloproliferative neoplasm. The disease-initiating event is the development of the Janus kinase (JAK2) V617F point mutation or JAK2 exon 12 mutation. This results in aberrant activation of JAK2 signaling, resulting in excess signal transduction via intracellular STAT5 signaling. The JAK2 mutation results in autonomous erythroid cell production. This leads to proliferation of erythroid precursors, with resultant increase in red blood cell production and increase in hemoglobin content. Greater than 95% of cases of polycythemia vera are due to the JAK2 mutation. Mutations in phosphoinositide-3-kinase (PI3K) and AKT have also been implicated in the pathophysiology of polycythemia vera but are less common.

Essential Thrombocythemia

The pathophysiology of essential thrombocythemia is most commonly due to either a mutation in one of 3 genes: JAK2, CALR, MPL. The pathophysiology of JAK2-mutation essential thrombocythemia is similar to JAK2-mutant polycythemia vera, except that the abnormal cell is the megakaryocyte in essential thrombocythemia. The JAK2 mutation accounts for 63% of essential thrombocythemia cases. The CALR mutation is second most common mutation in essential thrombocythemia and accounts for 23% of cases. The pathophysiology of CALR-mutant essential thrombocythemia involves a mutation in calreticulin, which is a chaperone protein in the endoplasmic reticulum. This mutation results in aberrant activation of the thrombopoietin receptor. The least common, yet well-defined, mutation in essential thrombocythemia is the MPL mutation. This accounts for 4% of essential thrombocythemia. The MPL gene encodes the thrombopoietin receptor, and a point mutation involving a tryptophan codon in the MPL gene causes excess activation of this receptor, resulting in excess platelet production.

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.

Primary Myelofibrosis

The pathophysiology of primary myelofibrosis is most commonly due to either a mutation in one of 3 genes: JAK2, CALR, MPL. The pathophysiology of JAK2-mutation primary myelofibrosis is similar to JAK2-mutant polycythemia vera, except that the abnormal cell is the megakaryocyte, which produces excess PDGF and TGF-beta and stimulates excess collagen production. The JAK2 mutation accounts for 59% of primary myelofibrosis cases. The CALR mutation is second most common mutation in primary myelofibrosis and accounts for 27% of cases. The pathophysiology of CALR-mutant primary myelofibrosis involves a mutation in calreticulin, which is a chaperone protein in the endoplasmic reticulum. This mutation results in aberrant activation of the thrombopoietin receptor. The least common, yet well-defined, mutation in essential thrombocythemia is the MPL mutation. This accounts for 7% of primary myelofibrosis cases. The MPL gene encodes the thrombopoietin receptor, and a point mutation involving a tryptophan codon in the MPL gene causes excess activation of this receptor, resulting in excess megakaryocyte-mediated PDGF and TGF-beta production, which creates bone marrow fibrosis.

Mastocytosis

The pathophysiology of mastocytosis, or mast cell neoplasm, has been largely unknown for decades. It was later discovered the mast cell arises from the common myeloid progenitor.

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