# HMGA Chromatin Remodeling Proteins in Tumor Progression in Myeloproliferative Neoplasms (MPN)

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $472,224

## Abstract

The goal of this proposal is to define the role of high mobility group A (HMGA) chromatin
remodeling proteins in tumor progression in myeloproliferative neoplasms (MPN). MPN are a
heterogeneous group of acquired, clonal hematopoietic stem and progenitor cell disorders characterized by
overproduction of mature blood cells and a propensity for leukemic transformation, although the molecular
mechanisms for tumor progression are unknown. Polycythemia vera (PV) is the prototypical MPN defined by
acquired activating mutations in the gene encoding JAK2, the obligate tyrosine kinase of hematopoietic growth
factor receptors for erythropoietin, G-CSF, and thrombopoietin, resulting in uncontrolled production of red cells,
white cells, and platelets. JAK2 mutations alone, however, do not account for progression from chronic, indolent
PV to acute leukemia. Importantly, outcomes for PV patients who progress to leukemia are abysmal; thus,
research is needed to determine how this occurs. Our scientific premise is based on compelling preliminary data
indicating that PV tumor progression is associated with overexpression in genes encoding the HMGA chromatin
binding proteins. HMGA proteins modulate gene expression by remodeling chromatin and recruiting
transcription factor complexes to DNA. Our group was the first to discover that HMGA genes function as potent
oncogenes that drive leukemic transformation in cultured cell models and transgenic mice. Moreover, HMGA
overexpression portends adverse clinical outcomes in diverse hematologic malignancies and solid tumors. In
diverse tumor models, we found that HMGA1 drives tumor progression through epigenetic alterations that induce
stem cell transcriptional networks. In preliminary data from ChIP-Seq in human CD34+ stem and progenitor
cells, we found that HMGA1 occupies promoter-enhancer regions for genes involved in self-renewal, de-
differentiation, inflammation, and myeloid leukemia. These exciting findings led us to the following hypotheses:
1) HMGA proteins are critical drivers of tumor progression in PV by inducing transcriptional networks that
maintain uncontrolled self-renewal, de-differentiation, and leukemic transformation, and, 2) Targeting HMGA
pathways will block tumor progression and reprogram advanced disease to a more indolent phenotype. We
have >600 primary human MPN tumors with detailed clinical annotation and genomic data and we generated
innovative mouse models to study HMGA in PV progression. Here, we propose to harness our unique models,
tumor samples, and expertise to elucidate the role of HMGA chromatin regulators in PV progression with the
following Specific Aims: 1) To determine whether HMGA overexpression predicts tumor progression and to
define cooperating genomic lesions and molecular mechanisms, 2) To define the functional significance of
HMGA in tumor progression in vivo using mouse models, and, 3) To investigate the clinical efficacy of targeting
HMGA pathways. Our work should uncover nove...

## Key facts

- **NIH application ID:** 10240323
- **Project number:** 5R01HL145780-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ALISON R MOLITERNO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $472,224
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240323

## Citation

> US National Institutes of Health, RePORTER application 10240323, HMGA Chromatin Remodeling Proteins in Tumor Progression in Myeloproliferative Neoplasms (MPN) (5R01HL145780-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10240323. Licensed CC0.

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