Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Aug 14;9(8):1901.
doi: 10.3390/cells9081901.

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

Julian Grabek  1   2 , Jasmin Straube  1   2 , Megan Bywater  1   2 , Steven W Lane  1   2   3
Affiliations
Review

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

Julian Grabek et al. Cells. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Adapted from [17] showing the frequency of each driver mutation in Myeloproliferative neoplasms (MPN) relative to the disease phenotype.
Figure 2
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
Figure 3
A proposed model for clonal evolution in MPN with acquisition of additional mutations leading to disease progression.
Figure 4
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.
See this image and copyright information in PMC

References

    1. Arber D.A., Orazi A., Hasserjian R., Thiele J., Borowitz M.J., Le Beau M.M., Bloomfield C.D., Cazzola M., Vardiman J.W. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–2405. doi: 10.1182/blood-2016-03-643544. - DOI - PubMed
    1. Heppner J., Nguyen L.T., Guo M., Naugler C., Rashid-Kolvear F. Incidence of myeloproliferative neoplasms in Calgary, Alberta, Canada. BMC Res. Notes. 2019;12:286. doi: 10.1186/s13104-019-4321-1. - DOI - PMC - PubMed
    1. Cerquozzi S., Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: A literature review of incidence and risk factors. Blood Cancer J. 2015;5:e366. doi: 10.1038/bcj.2015.95. - DOI - PMC - PubMed
    1. Tefferi A., Rumi E., Finazzi G., Gisslinger H., Vannucchi A.M., Rodeghiero F., Randi M.L., Vaidya R., Cazzola M., Rambaldi A., et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: An international study. Leukemia. 2013;27:1874–1881. doi: 10.1038/leu.2013.163. - DOI - PMC - PubMed
    1. Vannucchi A.M., Antonioli E., Guglielmelli P., Longo G., Pancrazzi A., Ponziani V., Bogani C., Ferrini P.R., Rambaldi A., Guerini V., et al. Prospective identification of high-risk polycythemia vera patients based on JAK2V617F allele burden. Leukemia. 2007;21:1952–1959. doi: 10.1038/sj.leu.2404854. - DOI - PubMed

Substances