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

Bridget K. Marcellino, Ronald Hoffman, Joseph Tripodi, Min Lu, Heidi Kosiorek, John Mascarenhas, Raajit K. Rampal, Amylou Dueck, Vesna Najfeld

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3581-3589
Number of pages9
JournalBlood advances
Volume2
Issue number24
DOIs
StatePublished - Dec 26 2018

Fingerprint

Chromosome Aberrations
Neoplasms
Proteins
Polycythemia Vera
Essential Thrombocythemia
Disease Progression
Blast Crisis
Tumor Suppressor Protein p53
Philadelphia Chromosome
Chromosomes, Human, Pair 12
Primary Myelofibrosis
Chromosomes, Human, Pair 17
Chromosomes, Human, Pair 1
Leukemia

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Marcellino, B. K., Hoffman, R., Tripodi, J., Lu, M., Kosiorek, H., Mascarenhas, J., ... Najfeld, V. (2018). Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53. Blood advances, 2(24), 3581-3589. https://doi.org/10.1182/bloodadvances.2018024018

Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53. / Marcellino, Bridget K.; Hoffman, Ronald; Tripodi, Joseph; Lu, Min; Kosiorek, Heidi; Mascarenhas, John; Rampal, Raajit K.; Dueck, Amylou; Najfeld, Vesna.

In: Blood advances, Vol. 2, No. 24, 26.12.2018, p. 3581-3589.

Research output: Contribution to journalArticle

Marcellino, BK, Hoffman, R, Tripodi, J, Lu, M, Kosiorek, H, Mascarenhas, J, Rampal, RK, Dueck, A & Najfeld, V 2018, 'Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53', Blood advances, vol. 2, no. 24, pp. 3581-3589. https://doi.org/10.1182/bloodadvances.2018024018
Marcellino, Bridget K. ; Hoffman, Ronald ; Tripodi, Joseph ; Lu, Min ; Kosiorek, Heidi ; Mascarenhas, John ; Rampal, Raajit K. ; Dueck, Amylou ; Najfeld, Vesna. / Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53. In: Blood advances. 2018 ; Vol. 2, No. 24. pp. 3581-3589.
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