A CRISPR/Cas9 engineered MplS504N mouse model recapitulates human myelofibrosis

Fabienne R. S. Adriaanse, Jennifer L. Kamens, Peter Vogel, Sadie M. Sakurada, Shondra M. Pruett-Miller, Ronald W. Stam, C. Michel Zwaan, Tanja A. Gruber

Research output: Contribution to journalComment/Letter to the editorAcademicpeer-review

2 Citations (Scopus)

Abstract

To the Editor:

The genetic etiology of clonal hematopoiesis characterizing >90% of all myeloproliferative neoplasms (MPNs) involve somatic mutations that induce signaling downstream of cytokine receptors and demonstrate significant overlap in clinical phenotype. Among these mutated genes is MPL, encoding for the thrombopoietin receptor which plays a central role in the regulation of megakaryopoiesis, HSC maintenance, and proliferation of progenitors. The most frequent MPL mutations, MPL S505N and MPL W515K/L/R/S/A, reside in exon 10 encoding for the transmembrane domain and lead to TPO-independent receptor activation. MPL W515K/L/R/S/A occurs at a much higher frequency in MPN, comprising 82% of MPL mutant cases in one study. These somatic mutations are often found in the heterozygous state, but homozygous mutations do occur in primary myelofibrosis (PMF), typically through acquired copy-neutral loss of heterozygosity. Both MPLS505N and MPLW515 mutations are also found as heterozygous autosomal dominant germline mutations with incomplete penetrance in hereditary thrombocytosis. To date, two studies have generated retroviral overexpression murine models to investigate the impact of human MPLW515 mutations on murine hematopoietic cells, both resulting in rapid onset of disease. However, the ability of the MPLS505N mutation has not yet been evaluated for its ability to perturb hematopoiesis, induce an MPN phenotype and recapitulate the pathology found in patients with MPL mutations. Herein, we describe a CRISPR/Cas9 engineered mouse model harboring a germline MplS504N mutation that can aid further investigation into the complex etiology of MPNs and essential thrombocythemia. [...]
Original languageEnglish
Pages (from-to)2535-2538
Number of pages4
JournalLeukemia
Volume36
Issue number10
Early online date23 Aug 2022
DOIs
Publication statusPublished - Oct 2022

Bibliographical note

Funding Information:
We thank the St. Jude Flow Cytometry and Cell Sorting Core, the Center for Advanced Genome Engineering, the Animal Research Center, the Transgenic/Gene Knockout Shared Resource and the Veterinary Pathology Core Laboratory. This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital.

Funding Information:
We thank the St. Jude Flow Cytometry and Cell Sorting Core, the Center for Advanced Genome Engineering, the Animal Research Center, the Transgenic/Gene Knockout Shared Resource and the Veterinary Pathology Core Laboratory. This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital.

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