# The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation: Diversity Supplement

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2020 · $60,099

## Abstract

PROJECT SUMMARY/ABSTRACT
Upregulated JAK/STAT signaling is considered a major factor driving the pathogenesis of myeloproliferative
neoplasms (MPNs). Clinically approved JAK inhibitors alleviate constitutional symptoms of MPNs, however
they do not alter underlying disease and do not target MPN-initiating malignant hematopoietic stem/ progenitor
cells (HSPCs). This observation suggests that alternative signaling pathways contribute to the pathogenesis of
MPNs. Detailing dysregulated pathways, besides JAK/STAT, that drive pathogenesis of MPNs specifically at
the MPN stem cell level, will inform new therapeutic strategies with possible curative potential. Evidence from
our laboratory indicates that loss of an adapter protein, Abelson interactor 1 (Abi-1), unexpectedly leads to
development of MPN-like disease in mice, and is mechanistically linked to hyperactivated STAT3 and NF-κB
signaling with only negligent upregulation of JAK2/STAT5 pathway. We also show that HSPCs and
granulocytes from patients with the most severe of MPNs - primary myelofibrosis (PMF) show decreased Abi-1
transcript and protein levels. To delineate mechanistic link between Abi-1, STAT3 and NF-κB signaling we
decided to use newest proximity-dependent labelling (PDL) technology in tandem with advanced proteomics to
provide in depth delineation of Abi-1 interactome (Specific Aim 2 of the parent grant). Our preliminary data
from this assessment, performed using cell line models stably expressing biotin ligase or biotin ligase
conjugated with Abi-1 subjected to PDL followed by mass spectrometry, identified components of the TAK1
(Map3k7) signaling pathway, including TAK1, Tab1, Tab2 and NF-κB1, in addition to well-established Abi-1
interactors such as WAVE2, Sra-1 or Nap1. These preliminary data point to TAK1 being a potential new link
between Abi-1 and NF-κB signaling pathways. Our central hypothesis is that Abi-1 plays an important and
potentially targetable role in HSPC self-renewal and differentiation via direct negative mechanistic regulation of
the STAT3/NF-κB inflammatory module of importance in MPN development. We will test this hypothesis in the
Specific Aim 1 of the proposed supplementary project where we will utilize our developed PDL
experimental tools, protocols and bioinformatic filtering strategy to establish STAT3 and NF-κB interactomes
and to identify common interactors linking Abi-1, STAT3 and NF-κB signaling in HSPCs. Achieving this goal
will not only allow us to determine mechanistic link between Abi-1/STAT3/NF-κB signaling axis newly
implicated in pathogenesis of MPNs, but also to identify potential new therapeutic targets. The significance of
our supplemental proposal relates to providing in depth assessment of a mechanistic cross-talk between
newly identified Abi-1/STAT3/NF-κB signaling axis and identify new targetable mechanisms and disease
drivers beyond JAK/STAT that contribute to malignant transformation of HSPCs, thereby leading to
development of PMF and ...

## Key facts

- **NIH application ID:** 10135225
- **Project number:** 3R01CA218079-02S1
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Patrycja Marta Dubielecka-Szczerba
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $60,099
- **Award type:** 3
- **Project period:** 2019-07-24 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135225

## Citation

> US National Institutes of Health, RePORTER application 10135225, The role of Abelson interactor 1 (Abi-1) in hematopoietic stem cell self-renewal and malignant transformation: Diversity Supplement (3R01CA218079-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10135225. Licensed CC0.

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