# Interrogating the Role of Abelson Interactor 1 in Age-Related Myelofibrosis

> **NIH NIH P20** · RHODE ISLAND HOSPITAL · 2020 · $220,180

## Abstract

PROJECT SUMMARY/ABSTRACT
Expansion and progressive displacement of hematopoietic stem/progenitor cells (HSPCs) from the bone
marrow to peripheral blood observed in primary myelofibrosis (PMF) suggests that aberrant communication
between stem cells and the bone marrow microenvironment (BMME) is key to understanding the etiology of
this disease. Molecular mechanisms that contribute to PMF pathology at the stem cell level are not known.
JAK/STAT cascade was found to be dysregulated in most PMF cases and in nearly all myeloproliferative
neoplasms (MPNs). However, the extent to which currently available inhibitors that target JAK/STAT pathway
alter the underlying disease and affect malignant hematopoietic stem cells is not clear. Our long term goal is
to better understand the molecular processes that control abnormal interactions between malignant HSPCs
and their BMME, and identify new targets for pharmacological intervention in PMF and other MPNs. The
overall objective of this application is to identify new signaling mechanisms involved in the initiation of age-
induced myelofibrosis and related MPNs. Our recent findings indicate that (1) conditional deletion of the gene
encoding the Abelson interactor-1 (Abi-1) adapter protein in mouse bone marrow induces myelofibrotic
phenotype, (2) hematopoietic progenitors and granulocytes from patients with PMF show decreased Abi-1
protein and transcript levels, (3) loss of Abi-1 positively affects activity of Src Family Kinases (SFKs) and their
downstream signaling to STAT3 and NFkB, and finally (4) loss of Abi-1 in malignant HSPCs leads to
dysregulation of adhesion and quiescence and induces their chemoresistance. Our central hypothesis is that
loss of Abi-1, through a positive effect on SFKs signaling and its downstream cross-talk with STAT3 and NFkB,
is a factor that initiates fibrosis-inducing changes at the malignant stem cell level. Our central hypothesis will be
tested in the following three Specific Aims. In Specific Aim 1 we will use our established Abi-1 conditional
bone marrow-specific mouse model (Abi-1 BM KO) to assess the effect of Abi-1 loss on the communication
between HSPCs and BMME and its role in the development of age-related myelofibrosis. In Specific Aim 2,
we will use advanced microscopy and biochemical arrays to elucidate the mechanism by which Abi-1 directly
controls SFKs and their downstream signaling to STAT3 and NFκB. In Specific Aim 3 using Abi-1 BM KO we
will evaluate the effects of SFKs inhibition on Abi-1-loss-induced myelofibrosis. Completion of these aims will
elucidate Abi-1-driven mechanisms that lead to the development of marrow fibrosis induced by malignant stem
cells in MPNs, and uncover potential new therapeutic approaches that directly address their pathogenesis. Our
strategy utilizes newly established animal models and has the potential to significantly advance the
understanding of tumor and stromal cell interactions. This knowledge will contribute to an emerging concep...

## Key facts

- **NIH application ID:** 9965981
- **Project number:** 5P20GM119943-04
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Patrycja Marta Dubielecka-Szczerba
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $220,180
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965981

## Citation

> US National Institutes of Health, RePORTER application 9965981, Interrogating the Role of Abelson Interactor 1 in Age-Related Myelofibrosis (5P20GM119943-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9965981. Licensed CC0.

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