Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms
Open accessAbstract
Significance: Myeloproliferative neoplasms (MPN) are chronic hematopoietic disorders characterized by clonal proliferation of mature myeloid elements. A subset of MPNs transforms to acute myeloid leukemia (AML). The mechanisms and pathways that contribute to transformation from MPN to AML have not been well delineated. We have characterized the somatic mutational spectrum of post-MPN AML and demonstrate that somatic tumor protein 53 ( TP53 ) mutations are common in JAK2 V617F - mutant, post-MPN AML but not in chronic-phase MPN. We demonstrate that expression of JAK2 V617F combined with Tp53 loss in a murine model leads to fully penetrant AML in vivo . We have characterized this model and used it to test therapeutic strategies. These data reveal novel insights into the pathogenesis of, and potential therapeutic strategies for, leukemic transformation.
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Deletion of Trp53 combined with JAK2 V617F mutation leads to highly penetrant myeloid leukemia in mice.
“Furthermore, deletion of Trp53 combined with JAK2 V617F mutation leads to highly penetrant myeloid leukemia in mice11,14.”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [11]
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Cites
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- Authors
- Rampal, R., Ahn, J., Abdel-Wahab, O., Nahas, M., Wang, K., Lipson, D., Otto, G. A., Yelensky, R., Hricik, T., McKenney, A. S., Chiosis, G., Chung, Y. R., Pandey, S., van den Brink, M. R. M., Armstrong, S. A., Dogan, A., Intlekofer, A., Manshouri, T., Park, C. Y., Verstovsek, S., Rapaport, F., Stephens, P. J., Miller, V. A., & Levine, R. L.
- Affiliations
- Human Oncology and Pathogenesis Program,
- Foundation Medicine (United States) (US)
- Program in Molecular Pharmacology and Chemistry,
- Departments of fImmunology,
- Pediatrics and Genetics (US)
- Pathology, and
- Memorial Sloan Kettering Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX 77030
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-12-02
- Volume
- 111
- Issue
- 50
- Pages
- E5401-10
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4273376
- OpenAlex
- W2031978224
- Cited by
- 301
- References
- 3
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 28 · 2023: 23 · 2022: 30 · 2021: 43 · 2020: 38 · 2019: 31 · 2018: 26 · 2017: 21 · 2016: 15 · 2015: 15 · 2012: 1
- FWCI
- 8.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leukemia and Lymphoma Society
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health (UL1TR000457)
- National Cancer Institute (R01CA151949, F30CA183497, R01CA172546, K08CA188529, R01CA155226, P01CA186866, P30CA008748, P30CA016672)
- National Institute of General Medical Sciences (T32GM007739)
- National Center for Research Resources (UL1RR024996)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- myeloproliferative neoplasms, leukemic transformation, acute myeloid leukemia, JAK2 V617F mutation, TP53 mutation, clonal dominance, megakaryocyte-erythroid progenitors, ruxolitinib, decitabine, PU-H71, Hsp90 inhibitors, JAK1/2 inhibitor, targeted therapy, xenograft mouse model
- MeSH terms
- Decitabine, Animals, Azacitidine, Colony-Forming Units Assay, Flow Cytometry, Humans, Myeloproliferative Disorders, Nitriles, Purines, Pyrazoles, Pyrimidines, Blotting, Western, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Hematologic Neoplasms, Mutation, Missense, Mice, Benzodioxoles, Janus Kinase 2, High-Throughput Nucleotide Sequencing, Exome
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