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Blood Adv. 2018 Dec 26;2(24):3581-3589. doi: 10.1182/bloodadvances.2018024018.

Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53.

Author information

1
Tisch Cancer Institute, Division of Hematology/Oncology, and.
2
Department of Pathology, The Icahn School of Medicine at Mount Sinai, New York, NY.
3
Division of Health Science Research, Section of Biostatistics, Mayo Clinic, Scottsdale, AZ; and.
4
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY.

Abstract

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (PMF), frequently progress to more overt forms of MF and a type of acute leukemia termed MPN-accelerated phase/blast phase (MPN-AP/BP). Recent evidence indicates that dysregulation of the tumor suppressor tumor protein p53 (TP53) commonly occurs in the MPNs. The proteins MDM2 and MDM4 alter the cellular levels of TP53. We investigated in 1,294 patients whether abnormalities involving chromosomes 1 and 12, which harbor the genes for MDM4 and MDM2, respectively, and chromosome 17, where the gene for TP53 is located, are associated with MPN disease progression. Gain of 1q occurred not only in individuals with MPN-BP but also in patients with PV and ET, who, with further follow-up, eventually evolve to either MF and/or MPN-BP. These gains of 1q were most prevalent in patients with a history of PV and those who possessed the JAK2V617F driver mutation. The gains of 1q were accompanied by increased transcript levels of MDM4 In contrast, 12q chromosomal abnormalities were exclusively detected in patients who presented with MF or MPN-BP, but were not accompanied by further increases in MDM2/MDM4 transcript levels. Furthermore, all patients with a loss of 17p13, which leads to a deletion of TP53, had either MF or MPN-AP/BP. These findings suggest that gain of 1q, as well as deletions of 17p, are associated with perturbations of the TP53 pathway, which contribute to MPN disease progression.

PMID:
30563882
PMCID:
PMC6306879
DOI:
10.1182/bloodadvances.2018024018
[Indexed for MEDLINE]
Free PMC Article

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