Myeloproliferative neoplasm pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The major clinical and pathologic findings in the myeloproliferative neoplasms (MPNs) are due to dysregulated proliferation and expansion of myeloid progenitors in the bone marrow, resulting in increased numbers of mature granulocytes, erythrocytes, or platelets in the peripheral blood.

Pathophysiology

Genetics

Although no specific genetic abnormalities or disease-initiating events have yet been identified for most of the MPNs, abnormal activation of tyrosine kinase-dependent signal transduction pathways are frequently implicated in their pathogenesis.

Chronic Myelogenous Leukemia

In chronic myelogenous leukemia, the Phialdelphia chromosome results in the formation of the BCR/ABL fusion gene which includes regions of the ABL gene translocated from chromosome 9 (region q34) to chromosome 22 (region q11), where they are juxtaposed with sequences of the BCR gene. The ABL protooncogene encodes a non-receptor tyrosine kinase involved in signal transduction and a variety of cellular processes including cell division, adhesion, differentiation, and response to stress. Juxtaposition of ABL with sequences of BCR results in enhanced tyrosine kinase activity and constitutive overactivity of tyrosine phosphokinase. In addition, the BCR/ABL protein leads to transactivation of Myc and BCL-2, which may protect the leukemic cells from apoptosis. Therefore the expansion of the neoplastic clone may be due not only to increased proliferation but also to prolonged survival.

Polycythemia Vera

In Polycythemia Vera, 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 MPNs remain to be seen. The events that lead to disease progression in any of the MPNs are poorly understood at the current time.

Myelofibrosis

One of the important bone marrow findings that overlaps the various MPNs 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.[1]

References

  1. Jaffe, Elaine (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon Oxford: IARC Press Oxford University Press (distributor. ISBN 978-9283224112.