# G0S2 in Chronic Myeloid Leukemia Disease Progression and Imatinib Resistance

> **NIH NIH K22** · TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO · 2020 · $195,590

## Abstract

PROJECT SUMMARY/ABSTRACT
Chronic myeloid leukemia (CML) is caused by BCR-ABL1, a constitutively active tyrosine kinase. The
development of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 has revolutionized the treatment of CML,
turning it from a fatal into a manageable chronic condition. Many patients respond favorably to TKIs, but some
patients do not achieve a response, and others lose their response, for an overall estimated failure rate of 20-
30% in chronic phase (CP-CML), and even higher rates in advanced CML. While TKI resistance is commonly
linked to point mutations in the BCR-ABL1 kinase domain, ~50% of clinical resistance cannot be explained by
BCR-ABL1 mutations, suggesting BCR-ABL1 kinase-independent resistance. Recurrence of active CML after
discontinuation of TKIs in responding patients is thought to reflect persistence of quiescent leukemic stem cells
(LSCs) that are innately resistant to TKIs despite BCR-ABL1 inhibition. Thus, understanding the molecular
mechanisms underlying BCR-ABL1 kinase-independent resistance will be critical to identify alternative treatment
strategies for patients with TKI resistance or advanced CML and to eradicate disease. Microarray data revealed
downregulation of G0S2 mRNA expression in CML CD34+ cells from imatinib non-responders (without
mutations) compared to responders, and in advanced disease compared to chronic phase. Preliminary data
suggests that G0S2 may play a role in both primary TKI resistance and in blastic transformation of CML. Specific
Aim 1: Determine whether G0S2 loss promotes TKI resistance and disease progression in CML. Data
from this aim will investigate the functional consequence of G0S2 loss in TKI resistance and blastic
transformation. We will assess the role of G0S2 in the growth, survival, and TKI sensitivity of CML cell lines and
primary CML CD34+ cells both in vitro and in vivo. We will also utilize a BCR-ABL1 transgenic mouse model and
G0S2 null mice to assess the role of G0S2 in CML leukemogenesis in vivo. Specific Aim 2: Identify the
mechanism by which loss of G0S2 induces TKI resistance in CML. G0S2 has been implicated in metabolic
pathway regulation, including fatty acid synthesis and oxidative phosphorylation. We have formed a collaborative
research team to rigorously establish the mechanistic role of G0S2 downregulation in TKI resistance. We will
address how reduced expression of G0S2 influences these metabolic pathways and, in turn, whether these
pathways alter imatinib response. Specific Aim 3: Determine the mechanism(s) by which G0S2 is
downregulated in TKI resistance and identify strategies to restore G0S2 expression. Data from this aim
will identify how G0S2 is downregulated in TKI resistance and blastic transformation, and will identify ways of
reprogramming TKI-resistant cells into a TKI-sensitive phenotype. We will investigate the potential role of
promoter hypermethylation and binding of transcriptional repressors, as well as the contribution of known
on...

## Key facts

- **NIH application ID:** 10223599
- **Project number:** 6K22CA216008-04
- **Recipient organization:** TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO
- **Principal Investigator:** Anna Marie Eiring
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,590
- **Award type:** 6
- **Project period:** 2018-09-10 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223599

## Citation

> US National Institutes of Health, RePORTER application 10223599, G0S2 in Chronic Myeloid Leukemia Disease Progression and Imatinib Resistance (6K22CA216008-04). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10223599. Licensed CC0.

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