# Investigation of ERBB2 and ERBB3 in hematopoiesis and predisposition to hematologic disease

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2021 · $172,530

## Abstract

Project Summary
 Rare inherited disorders provide unique opportunities to identify disease genes in humans, providing
insight into disease pathophysiology and often a better understanding of essential biological processes. This
can lead to improved diagnosis and treatment of patients with a broad range of disorders. The goal of this
proposal is to study the mechanisms underlying familial predisposition to hematological diseases such as
myelodysplastic syndrome (MDS) and the myeloproliferative neoplasms (MPN). These malignancies are
traditionally thought to occur due to acquired somatic mutations that become more frequent with age. However,
a growing body of evidence indicates that a significant number of patients harbor inherited genetic variants that
contribute to the onset of the malignant phenotype in adulthood. Understanding the etiology of this process
remains an important area of scientific research.
 Dr. Braunstein is a physician-scientist with a long-standing interest in human genetics. He obtained his
PhD in molecular genetics prior to entering clinical fellowship at Johns Hopkins School of Medicine. His
research efforts during his fellowship training led to the identification of ERBB3 as a novel candidate
predisposition gene in MDS. Upon completion of his fellowship, Dr. Braunstein joined the faculty in the Division
of Hematology at Johns Hopkins and initiated a research program to investigate genetic predisposition to
hematologic diseases. This grant will support Dr. Braunstein in his path toward becoming an independent
investigator and assist him in his goal of serving patients with rare inherited hematologic diseases.
 Previous work involving investigation of a large family with inherited erythroid MDS revealed a
missense mutation in the ERBB3 gene as the predisposing pathological variant. This data led to the premise
that mutations in ERBB3, or other ERBB genes, may occur in related diseases such as familial MPN, which
comprise approximately 10% of all MPN cases. This hypothesis is supported by the identification of a germline
variant in ERBB2 co-segregating with disease in a family with inherited MPN. The overarching hypothesis of
this application is that activation of the ERBB3 signaling pathway alters normal hematopoiesis and accelerates
clonal progression observed in hematologic malignancies such as MDS and MPN. Aim 1 proposes to analyze
the expression and function of the ERBB2 and ERBB3 genes in blood development using both primary
hematopoietic cells and an induced pluripotent stem cell (iPSC) model. Genetic modification of these cells will
be performed to isolate the role of these genes during hematopoiesis. The goal of Aim 2 is to investigate the
role of ERBB2 and ERBB3 in predisposition to MDS and MPN. Targeted sequencing of two patient cohorts
thought to be enriched for ERBB pathway mutations will be performed. Further, abnormal ERBB3 signaling in
the hematopoietic system will be studied using both a patient-derived iPSC m...

## Key facts

- **NIH application ID:** 10206238
- **Project number:** 5K08HL138142-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Evan M Braunstein
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $172,530
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206238

## Citation

> US National Institutes of Health, RePORTER application 10206238, Investigation of ERBB2 and ERBB3 in hematopoiesis and predisposition to hematologic disease (5K08HL138142-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10206238. Licensed CC0.

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