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
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: |
bioinformatics
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organism description > animal
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organism description > animal > mammal > rodent
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor |
| 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: |
11 Jan 2024 21:13 |
| PMCID: |
PMC9728578 |
| URI: |
https://repository.cshl.edu/id/eprint/40589 |
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