# Microenvironmental Regulation of Leukemia Stem Cells

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $352,688

## Abstract

PROJECT SUMMARY ABSTRACT
Chronic myelogenous leukemia (CML) results from hematopoietic stem cell (HSC) transformation by the BCR-
ABL oncogenic tyrosine kinase. Tyrosine kinase inhibitors (TKI) are highly effective in inducing remission and
prolonging survival in CML patients, but do not eliminate primitive, quiescent leukemia stem cells (LSC)
responsible for leukemia propagation and regeneration. As a result most patients experience rapid leukemia
relapse after TKI discontinuation. However, a subset of patients achieving prolonged, deep remission can
successfully discontinue TKI treatment without leukemia recurrence. Our research focuses on understanding
mechanisms of LSC resistance to TKI, and development of strategies to target LSC and their microenvironment
to prevent leukemia recurrence and enhance treatment free remission (TFR). We now understand that patients
achieving TFR continue to harbor small numbers of BCR-ABL+ LSC, suggesting that microenvironmental or
immune factor may regulate LSC potential to regenerate leukemia. The bone marrow (BM) microenvironment,
which includes diverse hematopoietic and non-hematopoietic cells, plays a critical role in HSC regulation. In
contrast, microenvironmental regulation of LSC growth is not well understood. Here we propose to characterize
critical niche regulatory mechanisms for maintenance of LSC, and that may contribute to leukemia recurrence
after stopping TKI treatment. We have shown that CML development leads to increased levels of several key
inflammatory cytokines in the BM, which can provide a selective growth advantage to CML LSC. Our preliminary
studies suggest that inflammatory signaling can modify CML BM MSC, resulting in enhanced support for CML
LSC, and reduced support of normal HSC. In Aim 1, we will explore the role of TNFa in mediating alterations in
BM MSC, resulting in increased expression of the inflammatory chemokine CXCL1 and enhanced signaling
through CXCR2 receptor, in LSC maintenance and leukemia regeneration after TKI treatment. Multipotent
mesenchymal stromal cells (MSC), identified on the basis of expression of LepR, nestin or Prx1, represent
specialized BM niches that maintain normal HSC. Our preliminary studies show that CXCL12 deletion from
Prx1+MSC leads to loss of LSC quiescence and enhanced sensitivity to TKI treatment. In Aim 2, we will
investigate mechanisms of regulation of LSC cycling and treatment resistance by CXCL12-expressing BM MSC
niches, focusing on regulation of EZH2 activity in LSC. We will also study the interaction between CXCL12 and
inflammatory signaling in modifying MSC niche function. These studies will be conducted using murine models
and primary human CML cells. Better understanding of mechanisms underlying microenvironmental regulation
of malignant stem cells will help guide development of novel strategies to enhance TFR in CML patients. We
further expect that the results of the proposed research will have broader implication towards other leukem...

## Key facts

- **NIH application ID:** 10169366
- **Project number:** 5R01CA172447-08
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** RAVI BHATIA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,688
- **Award type:** 5
- **Project period:** 2013-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169366

## Citation

> US National Institutes of Health, RePORTER application 10169366, Microenvironmental Regulation of Leukemia Stem Cells (5R01CA172447-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10169366. Licensed CC0.

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