# Identifying molecular markers that predict relapse after therapy discontinuation in chronic myeloid leukemia.

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2024 · —

## Abstract

The genome is relatively stable in chronic myeloid leukemia (CML), but mutation rates increase during
progression from chronic phase (CP) to blast crisis (BC). And, 30-50% of CML patients relapse in CP during
prolonged treatment with inhibitors of the Bcr-abl tyrosine kinase (TKIs). Relapse usually involves point mutations
in the BCRABL oncogene that impair TKI sensitivity, but many patients achieve remission after switching TKI.
Generation of reactive oxygen species (ROS) is relatively high in CML bone marrow, suggesting efficient ROS
handling may be required for low mutation rates in CP-CML during remission. CML neutrophils (PMNs) may
contribute to bone marrow ROS via the phagocyte-specific NADPH oxidase; activated during the innate immune
response. Consistent with this, we found aberrant activation of innate immune response pathways in human and
murine CML, and emergency (stress) granulopoiesis (EG) was sustained in CML mice. Failure to efficiently
terminate EG may favor mutagenesis by enhancing ROS production by CML-PMNs and expansion of leukemia
stem cells (LSCs) during this process. In a murine model of CML, we found that episodes of EG accelerated
TKI-resistance and BC compared to steady state. Oxr1 is the major mechanism for detoxifying PMN-ROS. Oxr1
has low (Oxr1S) and high efficiency (Oxr1L) isoforms. We found switch from Oxr1L to Oxr1S during EG in CML
mice but not Wt controls. Oxr1L also increased in CP relapse. Oxr1-knockdown in the bone marrow of CML mice
accelerated TKI-resistance and BC, consistent with a functional role for Oxr1 in leukemogenesis.
 Half of CML patients with a sustained major molecular response to TKI-treatment (<0.01% IS) remain in
remission after TKI-discontinuation. Unfortunately, molecular markers to predict relapse vs sustained therapy
free remission (TFR) are unknown. During the current funding period, we performed single cell RNA-Seq on
CD34+CD38- cells from a CML patient cohort undergoing therapy discontinuation. We identified interaction of
αβT cells and CML-LSCs in patients with relapse post TKI-discontinuation and in our murine CML model. T cell/
LSC interaction was not found with sustained TFR, or in second remission after failed discontinuation. T cell
interaction with CML cells were not previously described, but interaction with αβT cells facilitates intercellular
pathogen killing by phagocytes during the innate immune response. We found TFR was prolonged in mice
transplanted with single LSCs vs αβT cell/LSC doublets, or by treatment with an αβT cell antibody. These results
suggest a functional contribution of these T cells to LSC persistence and relapse post TKI-discontinuation.
 We hypothesize that dysregulation of the innate immune response in CML facilitates mutations that lead to
relapse or BC progression via inadequate ROS-handling and/or aberrant interaction of αβT cells with CML-LSCs.
The corollary to this hypothesis is that exposure of CML subjects to infectious challenge may enhance the ris...

## Key facts

- **NIH application ID:** 10797892
- **Project number:** 2I01CX001864-05A1
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Elizabeth Ann Eklund
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-04-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797892

## Citation

> US National Institutes of Health, RePORTER application 10797892, Identifying molecular markers that predict relapse after therapy discontinuation in chronic myeloid leukemia. (2I01CX001864-05A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10797892. Licensed CC0.

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