BMP2/SMAD pathway activation in JAK2/p53-mutant megakaryocyte/erythroid progenitors promotes leukemic transformation Journal Article
| Authors: | Li, B.; An, W.; Wang, H.; Baslan, T.; Mowla, S.; Krishnan, A.; Xiao, W.; Koche, R. P.; Liu, Y.; Cai, S. F.; Xiao, Z.; Derkach, A.; Iacobucci, I.; Mullighan, C. G.; Helin, K.; Lowe, S. W.; Levine, R. L.; Rampal, R. K. |
| Article Title: | BMP2/SMAD pathway activation in JAK2/p53-mutant megakaryocyte/erythroid progenitors promotes leukemic transformation |
| 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 population. Importantly, the bone morphogenetic protein 2/SMAD pathway is aberrantly activated during LT and results in abnormal self-renewal of megakaryocyte-erythroid progenitors. 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 show that this PEL is highly sensitive to combination WEE1 and poly(ADP-ribose) polymerase inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT and offer new, clinically translatable therapeutic approaches. © 2022 American Society of Hematology |
| Keywords: | myeloproliferative disorders; genetics; mutation; myeloproliferative disorder; janus kinase 2; mouse; animal; metabolism; animals; mice; protein p53; tumor suppressor protein p53; bone morphogenetic protein 2; megakaryocyte; megakaryocytes; megakaryocyte erythroid progenitor; bmp2 protein, mouse; megakaryocyte-erythroid progenitor cells |
| Journal Title: | Blood |
| Volume: | 139 |
| Issue: | 25 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2022-06-23 |
| Start Page: | 3630 |
| End Page: | 3646 |
| Language: | English |
| DOI: | 10.1182/blood.2021014465 |
| PUBMED: | 35421216 |
| PROVIDER: | scopus |
| PMCID: | PMC9728578 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
