Advisor(s)

Ravi Bhatia

Committee Member(s)

Craig Maynard
Lalita Shevde-Samnt
Laurie Harrington
Robert Welner

Document Type

Dissertation

Date of Award

1-29-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Joint Health Sciences

Abstract

Tyrosine kinase inhibition (TKI) is highly effective and promotes favorable long-term outcomes for many patients with chronic myeloid leukemia (CML). However, many patients experience treatment resistance or recurrence after TKI cessation due to leukemic stem cell (LSC) persistence within the hematopoietic stem cell (HSC) niche. Within the niche, macrophages adopt different activation states to alter HSC function, however, CML disrupts niche signals to selectively support LSCs and macrophages may contribute to this process. We hypothesize that macrophages contribute to pro-inflammatory activation within the niche to promote LSC development and nilotinib will reprogram macrophages to selectively support non-leukemic stem cells. To study this, we generated bone marrow chimeras by co-transplanting marrow cells from BCR::ABL1 transgenic mice and non-leukemic mice in a 1:1 ratio into sub-lethally irradiated recipients, with wild-type bone marrow chimeras as experimental controls. Upon achieving leukocytes counts upwards of 10x103 cells/µL with ≥ 40% neutrophils, animals were randomized with stratification for nilotinib and/or macrophage depletion. CML promoted the expansion of LSC-derived macrophages which had a characteristic overexpression of nitric oxide synthase driven by BCR::ABL. Moreover, CML macrophages significantly enhanced LSC expansion in vitro and in vivo. In contrast, TKI treatment attenuated the nitric oxide synthase response and promoted the expansion of non-leukemic macrophages paired with a subsequent reduction in BCR::ABL+ macrophages. TKI also maintained a subset of arginase 1 expressing immunomodulatory macrophages. Interestingly, we found that CML macrophages after TKI treatment selectively enhanced non-leukemic HSC expansion in vivo and in vitro. However, while LSC expansion was restricted, the response was similar to experimental controls suggesting that macrophages may contribute to LSC maintenance during TKI therapy. Together our results suggest that macrophages are crucial regulators of HSC and LSC fate and may be viable targets to augment the inhibition of BCR::ABL1 via TKI. Modulation of the macrophage response during TKI may enhance the elimination of LSCs to promote robust and durable molecular responses that may increase the probability of attaining treatment-free remission.

Keywords

BCR::ABL1;inflammation;inhibition;plasticity;tyrosine kinase

ProQuest Publication Number

32396606

ISBN

9798273399501

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