# Targeting DNA repair to eradicate TKi-refractory/resistant CML and Ph+ALL

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $387,997

## Abstract

Oncogenic BCR-ABL1 tyrosine kinase transforms hematopoietic stem cells (HSCs) to leukemia stem 
cells (LSCs) to induce chronic myeloid leukemia in chronic phase (CML-CP) and 
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). CML-CP may 
progress to more advanced accelerated phase (CML-AP), and subsequently to a very 
aggressive blast phase (CML-BP). Most CML/Ph+ALL patients are currently treated with 
tyrosine kinase inhibitors (TKis) such as imatinib, dasatinib and nilotinib. However, it 
is unlikely that TKis will “cure” CML/Ph+ALL patients due to the presence of TKi-refractory 
cells (e.g., quiescent LSCs), TKi-resistant cells (e.g., proliferating LSCs carrying BCR-ABL1 
kinase T315I mutant) and LSCs carrying additional somatic mutations. Therefore, novel treatment 
modalities are needed to eradicate TKi-refractory/resistant CML/Ph+ALL cells in the responding 
patients and to treat patients who do not respond favorably to TKis.
CML/Ph+ALL cells accumulate more DNA double strand breaks (DSBs), the most lethal DNA 
lesions, than normal counterparts. Leukemia cells can tolerate high numbers of DSBs because the 
repair mechanisms are altered and hyper-activated. Therefore, CML/Ph+ALL cells are “addicted” 
 to these pathways to survive pro-apoptotic challenge from high numbers of lethal DSBs. There 
are critical differences between DSB repair in normal and BCR-ABL1 leukemia cells. 
Proliferating LSCs usually employ RAD52-dependent DSB repairs and PARP1 –dependent 
alternative non-homologous end-joining (Alt-NHEJ), whereas normal counterparts use 
BRCA1/2-mediated homologous recombination (HR) and DNA-PKcs –dependent NHEJ (D-NHEJ). Quiescent 
LSCs use PARP1-mediated Alt-NHEJ instead of DNA-PKcs –dependent D-NHEJ, which is predominant in 
normal quiescent HSCs.
Research supported by previous award demonstrated that genetic and pharmacological 
targeting of PARP1 and/or RAD52 exerted synthetic lethal effect against BCR-ABL1 –positive 
leukemias. However, somatic mutations often detected in CMLs/Ph+ALLs not responding favorably 
 to TKi and/or progressing to more malignant stages can modulate the response to PARP1 and/or 
RAD52 inhibition.
We have discovered that DNA polymerase theta (Polθ, encoded by POLQ) plays a vital role in 
microhomology-mediated end-joining (MMEJ), a branch of Alt-NHEJ. Our preliminary data indicate 
that Polθ is essential for BCR-ABL1 –mediated leukemogenesis and that targeting of Polθ eliminated 
CML/Ph+ALL cells. Aim #1 is designed to determine if/how BCR-ABL1 –mediated signaling modifies Polθ 
to regulate its biological activities and to pinpoint the role of Polθ in CML and Ph+ALL stem 
cells. Aim #2 will optimize Polθ inhibitor (Polθi) to be suitable for in vivo use. Aim #3 is 
focused on genetic and pharmacological targeting of Polθ and/or PARP1 and RAD52 against TKi-naive 
and TKi-treated CMLs/Ph+ALLs in in vitro conditions mimicking peripheral blood and bone 
marrow microenvironment and also in vivo...

## Key facts

- **NIH application ID:** 10114978
- **Project number:** 5R01CA186238-07
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** TOMASZ SKORSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,997
- **Award type:** 5
- **Project period:** 2014-08-12 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114978

## Citation

> US National Institutes of Health, RePORTER application 10114978, Targeting DNA repair to eradicate TKi-refractory/resistant CML and Ph+ALL (5R01CA186238-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114978. Licensed CC0.

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