Abstract
The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis share driver mutations that either activate the thrombopoietin receptor, MPL, or indirectly activate it through mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, although the myeloproliferative neoplasms are classified as neoplasms because they are clonal hematopoietic stem cell disorders, the mutations affecting MPL or JAK2 are gain-of-function, resulting in increased production of normal erythrocytes, myeloid cells and platelets. Constitutive JAK2 activation provides the basis for the shared clinical features of the myeloproliferative neoplasms. A second molecular abnormality, impaired posttranslational processing of MPL is also shared by these disorders but has not received the recognition it deserves. This abnormality is important because MPL is the only hematopoietic growth factor receptor expressed in hematopoietic stem cells; because MPL is a proto-oncogene; because impaired MPL processing results in chronic elevation of plasma thrombopoietin, and since these diseases involve normal hematopoietic stem cells, they have proven resistant to therapies used in other myeloid neoplasms. We hypothesize that MPL offers a selective therapeutic target in the myeloproliferative neoplasms since impaired MPL processing is unique to the involved stem cells, while MPL is required for hematopoietic stem cell survival and quiescent in their bone marrow niches. In this review, we will discuss myeloproliferative neoplasm hematopoietic stem cell pathophysiology in the context of the behavior of MPL and its ligand thrombopoietin and the ability of thrombopoietin gene deletion to abrogate the disease phenotype in vivo in a JAK2 V617 transgenic mouse model of PV.
Highlights
The myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), are hematopoietic stem cell (HSC) disorders that express mutations activating JAK2 [1,2,3,4], the cognate tyrosine kinase for the type 1 homodimeric hematopoietic growth factor receptors for erythropoietin (EPO) and thrombopoietin (THPO)Myeloproliferative Neoplasms Are Thrombopoietin-Dependent Diseases [5], and the granulocyte-colony stimulating factor receptor as well [6]
Because MPL is essential for HSC quiescence and survival in the marrow osteoblastic niche [22, 23, 67] and is responsible for THPO catabolism [57], we hypothesized that impaired MPL cellsurface expression was essential for MPN phenotypic behavior, causing unregulated hematopoietic progenitor cell (HPC) proliferation and, eventually, myelofibrosis due to increased plasma THPO [30], depending on the MPN driver mutation allele burden, while causing HSC loss from the marrow [22]
Restoration of one THPO allele completely restored the PV phenotype, in contrast to the incomplete restoration of the PV phenotype with a single MPL gene (JAK2 V617/MPL del/+). These results indicate that constitutive MPL signaling through JAK2 V617F alone was not sufficient to support the full PV phenotype in this transgenic mouse model
Summary
The myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), are hematopoietic stem cell (HSC) disorders that express mutations activating JAK2 [1,2,3,4], the cognate tyrosine kinase for the type 1 homodimeric hematopoietic growth factor receptors for erythropoietin (EPO) and thrombopoietin (THPO). Myeloproliferative Neoplasms Are Thrombopoietin-Dependent Diseases [5], and the granulocyte-colony stimulating factor receptor as well [6] These disorders are genetically distinct [7, 8] [9], have different natural histories [10], different complications and require different therapies [11], they exhibit significant clinical phenotypic mimicry, including overproduction of one or more blood cell types alone or together, extramedullary hematopoiesis (EMH) and transformation to myelofibrosis or to acute leukemia [12]. We discuss how the unique dependence of HSC on the MPL–THPO axis together with the unusual pathophysiology of MPL in the MPN, creates a therapeutic target of opportunity to suppress MPN HSC while sparing normal HSC
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