Myeloproliferative Neoplasms: Diseases Mediated by Chronic Activation of Signal Transducer and Activator of Transcription (STAT) Proteins

Abstract

Myeloproliferative neoplasms (MPNs) are hematopoietic diseases characterized by the clonal expansion of single or multiple lineages of differentiated myeloid cells that accumulate in the blood and bone marrow. MPNs are grouped into distinct categories based on key clinical presentations and distinctive mutational hallmarks. These include chronic myeloid leukemia (CML), which is strongly associated with the signature BCR::ABL1 gene translocation, polycythemia vera (PV), essential thrombocythemia (ET), and primary (idiopathic) myelofibrosis (PMF), typically accompanied by molecular alterations in the JAK2, MPL, or CALR genes. There are also rarer forms such as chronic neutrophilic leukemia (CNL), which involves mutations in the CSF3R gene. However, rather than focusing on the differences between these alternate disease categories, this review aims to present a unifying molecular etiology in which these overlapping diseases are best understood as disruptions of normal hematopoietic signaling: specifically, the chronic activation of signaling pathways, particularly involving signal transducer and activator of transcription (STAT) transcription factors, most notably STAT5B, leading to the sustained stimulation of myelopoiesis, which underpins the various disease sequalae.

Keywords: BCR-ABL1; CALR; CML; CNL; CSF3R; ET; JAK2; MPL; MPN; PMF; PV; STAT5.

Figure 1

Normal myelopoiesis. The various myeloid cell lineages develop from a common myeloid progenitor through a series of distinct lineage commitment steps with increased differentiation and decreased proliferation as development proceeds.

Figure 2

Role of cytokine receptor signaling in myelopoiesis. Distinct cytokine receptors influence the production of specific myeloid cell lineages: the erythropoietin receptor (EPO-R, red) for erythrocytes (A), the thrombopoietin receptor (TPO-R/MPL, orange) for megakaryocytes/platelets (B), and the granulocyte colony-stimulating factor receptor (G-CSF-R/CSF3R, blue) for neutrophils (C). This is mediated by associated Janus kinase (JAK1 and JAK2, green) protein tyrosine kinases and cytoplasmic signal transducer and activator of transcription (STAT3 and STAT5, brown) transcription factors, which are activated transiently when the relevant cytokine (gray) binds to its receptor to influence the production of the indicated myeloid lineage.

Figure 3

Impact of MPN-associated mutations. Mutations (black stars) can affect the JAK2 protein associated with EPO-R (red), TPO-R/MPL (orange), and G-CSF-R/CSF3R (blue), and calreticulin (CALR) that is associated with TPO-R/MPL, as well as TPO-R/MPL or G-CSF-R/CSF3R themselves, or generate the novel BCR-ABL1 oncoprotein. In each case this leads to chronic activation of STAT proteins, predominantly STAT5. This results in enhanced transcription of a variety of genes that stimulate the excessive myelopoiesis that is associated with all categories of MPNs.