BMP2/SMAD pathway activation in JAK2/p53-mutant Megakaryocyte/Erythroid Progenitors Promotes Leukemic Transformation

Li, Bing, An, Wenbin, Wang, Hua, Baslan, Timour, Mowla, Shoron, Krishnan, Aishwarya, Xiao, Wenbin, Koche, Richard Patrick, Liu, Ying, Cai, Sheng F, Xiao, Zhijian, Derkach, Andriy, Iacobucci, Ilaria, Mullighan, Charles G, Helin, Kristian, Lowe, Scott W, Levine, Ross L, Rampal, Raajit K (April 2022) BMP2/SMAD pathway activation in JAK2/p53-mutant Megakaryocyte/Erythroid Progenitors Promotes Leukemic Transformation. Blood. ISSN 0006-4971

URL: https://www.ncbi.nlm.nih.gov/pubmed/35421216
DOI: 10.1182/blood.2021014465

Abstract

Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) has a dismal prognosis and is largely fatal. Mutational inactivation of TP53 is the most common somatic event in LT, however the mechanisms by which TP53 mutations promote LT remain unresolved. Using an allelic series of mouse models of Jak2/Trp53 mutant MPN, we identify that only biallelic inactivation of Trp53 results in LT (to a pure erythroleukemia (PEL)). This PEL arises from the megakaryocyte erythroid progenitor (MEP) population. Importantly, the BMP2/SMAD pathway is aberrantly activated during LT, and results in abnormal self-renewal of MEPs. Finally, we identify that Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage. Using a synthetic-lethality strategy, by targeting active DNA-repair pathways, we demonstrate that this PEL is highly sensitive to combination WEE1 and PARP inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT, and offer new, clinically-translatable therapeutic approaches.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies
CSHL Authors:
Communities: CSHL labs > Lowe lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 14 April 2022
Date Deposited: 20 Apr 2022 14:30
Last Modified: 20 Apr 2022 14:30
URI: https://repository.cshl.edu/id/eprint/40589

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