MPN: The Molecular Drivers of Disease Initiation, Progression and Transformation and their Effect on Treatment

Abstract

Myeloproliferative neoplasms (MPNs) constitute a group of disorders identified by an overproduction of cells derived from myeloid lineage. The majority of MPNs have an identifiable driver mutation responsible for cytokine-independent proliferative signalling. The acquisition of coexisting mutations in chromatin modifiers, spliceosome complex components, DNA methylation modifiers, tumour suppressors and transcriptional regulators have been identified as major pathways for disease progression and leukemic transformation. They also confer different sensitivities to therapeutic options. This review will explore the molecular basis of MPN pathogenesis and specifically examine the impact of coexisting mutations on disease biology and therapeutic options.

Keywords: CALR; DNA methylation; IFNα; JAK2; MPL; MPN; chromatin modifiers; driver mutations; leukemic transformation; myeloproliferation; spliceosome; transcriptional regulators; tumour suppressors.

Figure 1

Adapted from [17] showing the frequency of each driver mutation in Myeloproliferative neoplasms (MPN) relative to the disease phenotype.

Figure 2

The molecular signalling pathways involved in MPN: The cell surface receptors are erythropoietin receptor (EPOR; red) and thrombopoietin receptor/MPL (navy blue), MPL with mutated Calreticulin (CALR), wildtype MPL with no ligand (thrombopoietin (TPO)) bound and no STAT signalling, wildtype EPOR with bound ligand (erythropoietin (EPO)) leading to STAT signalling, EPOR with JAK2 mutant, MPL with JAK2 mutant and mutated MPL. The cytoplasm shows STAT pathway signalling with activation of phosphatidylinositol 3-kinase (PI3K)/Akt and RAS pathways, and the nucleus (lilac background) shows the effects of driver and coexisting mutations on nuclear functions. Headings for DNA methylation modifiers, tumour suppressors, transcription regulators, spliceosome complex and chromatin modification identify the key sites of coexisting mutations. Abbreviations not mentioned in the body of the article: STAT, signal transducers and activators of transcription; PI3K, phosphatidylinositol 3-kinase; Akt, Protein kinase B; mTOR, mammalian target of rapamycin; SUZ12, suppressor of zeste 12 homolog; EEZ, embryonic ectoderm development; BAP1, BRCA1-associated protein 1; BRD4, bromodomain containing protein 4; BCL-2, B cell lymphoma 2; BCL-XL, B cell lymphoma extra large; Ac, acetylated; Me, methylated; Ub, ubiquitinated; P, phosphorylated; mut, mutated.

Figure 3

A proposed model for clonal evolution in MPN with acquisition of additional mutations leading to disease progression.

Figure 4

Treatments in MPN and the mechanism of action to control the disease through DNA damage, signalling and proliferation and cell cycle and self-renewal effects: Toxic symbol, chemotherapeutic agents; JAKi, JAK inhibitor; IRF9, interferon regulatory factor 9; ISGs, interferon-stimulated genes; TYK2, tyrosine kinase 2.