High Mobility Group A Chromatin Regulators: Key Epigenetic Switches and Therapeutic Targets Required for MPN Progression

New research shows that high mobility group A1/2 (HMGA1/2) genes are overexpressed in MPN with highest levels in more advanced diseases such as myelofibrosis (MF), and acute myeloid leukemia (AML). The findings were presented at the 12^th International Congress on Myeloproliferative Neoplasms.

 In this study, researchers compared HMGA1/2 in JAK2V617F mutant AML cell lines from MPN patients (DAMI, SET-2), CD34+ cells from PV patients during chronic and transformation phases, and JAK2V617F mouse models of PV (transgenic JAK2V617F) and PVAML (transgenic JAK2V617F/MPLSV).

They noted that in order elucidate HMGA1/2 function, they silenced HMGA1 or HMGA2 via short hairpin RNA in human MPN-AML cells and subsequently generated murine models of PV and PV-AML with heterozygous Hmga1 or Hmga2 deficiency. Moreover, the researchers compared RNA-Seq from MPN-AML cell lines after gene silencing to assess molecular mechanisms underlying HMGA.

The results of the study showed that HMGA1/2 mRNA are up-regulated in all JAK2V617F-positive contexts, including primary human PV CD34+ cells and total bone marrow from JAK2V617F mouse models for PV compared to controls. Also, the researchers observed a marked up-regulation in HMGA1/2 in CD34+ cells from PV patients after transformation to MF or AML and in leukemic blasts from our PV-AML mouse model. The results further displayed that silencing HMGA1 or HMGA2 in human MPN-AML cell lines significantly halts proliferation, disrupts clonogenicity, and prevents leukemia development in mice.

“In JAK2V617F murine models, heterozygous deficiency of Hmga1 prevents MPN progression to MF and prolongs survival in a fulminant MPN-AML model,” the research authors wrote.  “Moreover, RNA-Seq analyses indicates that HMGA amplifies transcriptional networks involved cell cycle progression, which can be targeted with epigenetic therapies.”

They also said that their findings “further underscore the key role for HMGA as an epigenetic switch required for transformation in MPN and opens the door to novel therapeutic approaches to prevent disease progression.”

Resar L, et al. High Mobility Group A Chromatin Regulators: Key Epigenetic Switches and Therapeutic Targets Required for MPN Progression. Presented at the 12^th International Congress on Myeloproliferative Neoplasms; October 24-25, 2019; New York, NY.