Myeloproliferative neoplasm stem cells

Abstract

Myeloproliferative neoplasms (MPNs) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that provides a selective advantage to mutant HSC over normal HSC and promotes myeloid differentiation to engender a myeloproliferative phenotype. This population of somatically mutated HSC, which initiates and sustains MPNs, is termed MPN stem cells. In >95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in 1 of 3 genes: JAK2, CALR, or MPL The thrombopoietin receptor, MPL, is the key cytokine receptor in MPN development, and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells. Despite common biological features, MPNs display diverse disease phenotypes as a result of both constitutional and acquired factors that influence MPN stem cells, and likely also as a result of heterogeneity in the HSC in which MPN-initiating mutations arise. As the MPN clone expands, it exerts cell-extrinsic effects on components of the bone marrow niche that can favor the survival and expansion of MPN stem cells over normal HSC, further sustaining and driving malignant hematopoiesis. Although developed as targeted therapies for MPNs, current JAK2 inhibitors do not preferentially target MPN stem cells, and as a result, rarely induce molecular remissions in MPN patients. As the understanding of the molecular mechanisms underlying the clonal dominance of MPN stem cells advances, this will help facilitate the development of therapies that preferentially target MPN stem cells over normal HSC.

Figure 1.

Key somatic mutations and growth factor receptors important for MPN development. (A) Simplified “roadmap” of hematopoietic development. (B) Distribution of key growth factor receptors in different stem, progenitor, and precursor cell populations. For each population, potential impact of JAK2V617F, CALR, or MPL mutation is indicated.

Figure 2.

Key steps during MPN development from normal hematopoiesis following acquisition of an MPN-initiating mutation in a single HSC. The mutant HSC acquires a selective advantage over normal HSC and also promotes myeloid differentiation, eventually leading to a myeloproliferative phenotype. The expanded, abnormal myeloid clone disrupts the bone marrow microenvironment, promoting a self-reinforcing malignant niche that favors MPN stem cells over normal HSC and leads to eventual mobilization of MPN HSC into the peripheral blood (PB).

Figure 3.

Summary of the factors that influence phenotypic heterogeneity in MPNs.

Figure 4.

Disease heterogeneity following acquisition of the JAK2V617F mutation in a single HSC. X-axis represents time following acquisition of JAK2V617F indicated by the arrow. Y-axis represents relative contribution from this HSC clone to each lineage, indicated by color. (A) JAK2V617F occurs in a platelet-biased HSC resulting in ET. (B) JAK2V617F occurs in a lineage-balanced HSC resulting in PV with trilineage myeloproliferation. (C) JAK2V617F occurs in an HSC with limited self-renewal capability resulting in CHIP. (D) JAK2V617F precedes acquisition of a TET2 mutation resulting in a PV phenotype. (E) TET2 precedes acquisition of a JAK2V617F mutation resulting in an ET phenotype. (A-C) represent hypotheses to explain how HSC heterogeneity may influence MPN phenotype. (D-E) represent an interpretation of published data demonstrating that the order in which JAK2V617F and TET2 mutations are acquired influences MPN phenotype.