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

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.

Patient Similarity Network of Newly Diagnosed Multiple Myeloma Identifies Patient Sub-groups with Distinct Genetic Features and Clinical Implications

“…The most significant findings of our study involve the gain of the long arm of chromosome 1, a high-risk feature observed in ~40% of MM cases and in several other types of cancer, including breast cancer, hepatocellular carcinoma and myeloproliferative neoplasms [38][39][40][41] . Patients affected by monoclonal gammopathy of undetermined significance (MGUS), a precursor of MM, and smoldering MM (SMM) who carry gain(1q) have higher risk of progression to MM, with a median time to progression of two years 42,43 .…”

Impact of Integrated Genetic Information on Diagnosis and Prognostication for Myeloproliferative Neoplasms in the Next-Generation Sequencing Era

“…Studies have shown that TP53 mutations occur at a low frequency in chronic-phase MPNs and increase signi cantly according to disease progression. TP53 mutations were positively correlated with poor survival outcomes, including early death [4,5,21], and − 7/del(7q) was associated with poor survival in PMF patients [32]. Because all patients with TP53 mutations had a complex karyotype, we postulated that presence of TP53 mutation resulted from accumulation of genetic aberrations through disease progression.…”

“…Important gene mutations associated with patient outcomes, such as mutations in TP53 and ASXL1, have been identi ed using NGS approaches. [4][5][6][7][8] Risk strati cation of MPNs is based on clinical and hematologic features. Advanced age, leukocytosis, and venous thrombosis are considered risk factors for survival in PV [9] and ET [10].…”

Patient Similarity Network of Multiple Myeloma Identifies Patient Sub-groups with Distinct Genetic and Clinical Features

“…In particular, co-occurrence of gain(1q) with the t(4;14) MMSET translocation was significantly enriched in subgroup 2e and was the most significant and frequent event associated with poor outcome, as further confirmed in an independent dataset. Gain(1q) is observed in ~40% of MM cases and in several other types of cancer, including breast cancer, hepatocellular carcinoma and myeloproliferative neoplasms, and has been the subject of numerous studies in the past decade [40][41][42][43] . A recent study has shown that newly diagnosed MM patients with gain of 1q who received induction therapy with bortezomib, lenalidomide and dexamethasone (VRD) are at higher risk of early relapse, especially when amp(1q) is detected 28 .…”