How to drug a leukemic stem cell: deciphering heterogeneity for better specificity



Review

. 2025 Jul 25;2(4):100146.


doi: 10.1016/j.bneo.2025.100146.


eCollection 2025 Nov.

Affiliations

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Review

Alice Worker et al.


Blood Neoplasia.


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Abstract

Blood cancers, such as acute myeloid leukemia (AML), are becoming increasingly common due to an aging population but remain challenging to treat. Relapse is the most important singular cause of treatment failure in AML, and up to half of patients relapse after chemotherapy or bone marrow transplantation. Relapse in AML is primarily due to a population of quiescent leukemic stem cells (LSCs) that shelter in the bone marrow. Chemotherapy hits actively proliferating AML blasts, but LSCs escape and can later re-enter the cell cycle to regenerate the leukemia. LSCs resemble hematopoietic stem cells, but variable and unique differences may allow for LSC-specific treatment. In this review, we summarize the unique biology of LSCs, considering both global and subtype-specific traits. We describe how heterogeneity, both between different AML subtypes and within the LSC compartment, has impaired efforts to find drug targets so far and how this is being resolved with technological advances such as single-cell sequencing. We elucidate which aspects of LSC biology determine possibilities for targeted treatment and the progress so far made toward therapies to prevent or treat relapse.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures


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Graphical abstract


Figure 1.



Figure 1.

Summary of potential factors underlying relapse likelihood.


Figure 2.



Figure 2.

Metabolism, proteostasis, and signaling together regulate the balance of growth, quiescence, and cell survival in LSCs. Both cell-intrinsic (light pink background) and -extrinsic bone marrow niche factors (dark pink background) are able to influence a range of effects on LSCs, contributing to antiapoptotic and drug resistance promoting signaling. Dashed lines indicate mechanisms known to have subtype-specific regulation; solid lines indicate mechanisms for which no subtype-specific regulation known at this time. ER, endoplasmic reticulum; OXPHOS, oxidative phosphorylation.

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