# Oncogenic Nras signaling in leukemic stem cell transformation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $387,500

## Abstract

ABSTRACT
Mutations of oncogenes and tumor suppressor genes transform normal hematopoietic stem
cells (HSC) into leukemic stem cells (LSC) in a multi-step process. As the first step of
leukemogenesis, the “pre-leukemia” mutations dys-regulate HSC functions to promote clonal
expansion by increasing proliferation, competitiveness and self-renewal. Pre-LSCs are further
transformed into LSCs by additional mutations. Targeting pre-LSCs and LSCs has the potential
to eliminate leukemia. Although many oncogenes and tumor suppressor genes have been
proposed to transform normal HSCs to LSCs, very little is known about what signaling
mechanism underlies this transformation to allow development of therapies to target pre-LSCs
and LSCs. The long term goal of our research is to identify signaling mechanisms through which
oncogenes and tumor suppressor genes transform normal HSCs into LSCs. Clonal expansion
has been difficult to recapitulate experimentally because mutations that drive HSCs into cycling
often lead to reduced HSC self-renewal and HSC depletion. We recently found that an
oncogenic Nras mutation commonly found in human leukemias, G12D, dys-regulates HSCs and
transform them into pre-LSC with increased proliferation, competitiveness and self-renewal. The
objective of this proposal is to identify the signaling mechanism underlying this Nras induced
transformation. Based on our preliminary results, our central hypothesis is that JAK2/STAT5
signaling is critical in the Nras induced transformation to pre-LSCs and further mediates
transformation to LSCs. We will test this hypothesis by 1) Identify the mechanism by which
NrasG12D activates STAT5 to dys-regulate HSC functions; 2) Define the role of JAK2 in NrasG12D
induced HSC dys-regulation and 3) determine the role of JAK2/STAT5 signaling in fully
transformed LSCs. The approach is innovative because 1) it takes advantage of our newly
developed clonal expansion model; 2) it combines mouse genetic analysis and cellular and
biochemical analysis on rare populations to investigate signaling mechanisms in pre-LSCs and
LSCs, and 3) it evaluates the role of non-canonical Ras effectors that may be responsible for
the effects of oncogenic Ras in a population highly relevant to leukemogenesis. The proposed
research is significant because it is expected to advance knowledge of the signaling
mechanisms underlying the transformation from normal HSCs to LSCs, and therefore to inform
novel therapeutic intervention that will target pre-LSCs and LSCs to eradicate leukemia.

## Key facts

- **NIH application ID:** 9858411
- **Project number:** 5R01HL132392-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Qing Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2016-03-01 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858411

## Citation

> US National Institutes of Health, RePORTER application 9858411, Oncogenic Nras signaling in leukemic stem cell transformation (5R01HL132392-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9858411. Licensed CC0.

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