# Developing a novel therapeutic strategy for overcoming TKI resistance in ALL

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $487,847

## Abstract

Nearly one-third of adult patients with acute lymphoblastic leukemia (ALL) are associated with the
t(9;22) chromosomal translocation that forms the BCR-ABL oncogene. BCR-ABL induces B-cell acute
lymphoblastic leukemia (B-ALL) directly or in acute blastic phase advanced from chronic phase myeloid
leukemia. Compared to other types of B-ALL, BCR-ABL-positive B-ALL has a poor prognosis and is much
less sensitive to tyrosine kinase inhibitors (TKIs) even in the absence of BCR-ABL kinase mutations, and
the underlying mechanisms for this type of the TKI-resistance are largely unknown. We hypothesize that
there must be critical downstream pathways whose activation by BCR-ABL is required for B-ALL
development but cannot be completely shut down through inhibition of BCR-ABL kinase activity by TKIs,
suggesting a BCR-ABL kinase-independent mechanism different from the TKI resistance induced by BCR-
ABL kinase domain mutations. This novel idea is supported by our preliminary findings that arachidonate
15-lipoxygenase (Alox15) is upregulated by BCR-ABL and required for B-ALL development in mice but this
Alox15 upregulation is not reversed by inhibiting BCR-ABL kinase activity with imatinib (a TKI). These
preliminary findings link Alox15 to TKI resistance in B-ALL cells, providing a new strategy for overcoming
TKI resistance in treating BCR-ABL-positive B-ALL and strategically other leukemias induced by oncogenic
tyrosine kinases. We should mention that it is totally unknown about how the Alox15 pathway mediates TKI
resistance in B-ALL, and a better understanding of this Alox15-mediated TKI resistant mechanism requires
demonstration of an essential role of Alox15 in B-ALL induced by BCR-ABL and in-depth mechanistic
studies that lead to a full understanding of Alox15-associated pathways and their contributions to B-ALL
development. Without any doubt, these studies will help to develop a new therapeutic strategy for
overcoming TKI resistance in treating BCR-ABL-positive B-ALL by targeting the Alox15 pathway.
Specifically, by mainly taking a genetic approach using gene knockout mice and CRISPR-Cas9 technology,
we will test our hypothesis by revealing the roles of Alox15 and its related pathways in B-ALL development
and in the response of B-ALL cells to TKIs. If successful, the results will have a huge impact on our better
understanding of disease mechanisms for B-ALL and help to identify novel targets in treating TKI-insensitive
human B-ALL that still lacks effective therapies. The specific aims are: 1) To investigate the role of Alox15
lipid metabolites in promoting growth and inducing TKI resistance of B-ALL cells; 2) To study the roles of
Alox15-regulated key partner genes in BCR-ABL-induced B-lymphoid transformation and resistance of
leukemia cells to TKIs; and 3) To develop a therapeutic strategy for circumventing TKI resistance in human
B-ALL by inhibiting the Alox15 pathway.

## Key facts

- **NIH application ID:** 10057364
- **Project number:** 5R01CA222590-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Shaoguang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $487,847
- **Award type:** 5
- **Project period:** 2017-12-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057364

## Citation

> US National Institutes of Health, RePORTER application 10057364, Developing a novel therapeutic strategy for overcoming TKI resistance in ALL (5R01CA222590-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10057364. Licensed CC0.

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