ATP-binding cassette transporters have long been cast in a familiar role in leukemia biology: molecular pumps embedded in the cell membrane that spit chemotherapy drugs back out before they can do their work. A new review argues that this decades-old picture is due for a major revision. Writing in the journal Medical Oncology, researchers from Banaras Hindu University and Multanimal Modi College in India synthesize recent mechanistic and translational evidence showing that the best-known ABC transporters—ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP)—are not simply static overexpressed pumps, but dynamic components of an integrated resistance network wired into stress signaling, metabolism, and the protective architecture of the bone marrow microenvironment.

The review, authored by Jyotirmayee, Veerandra Kumar, and Malkhey Verma, consolidates findings across the major leukemia subtypes, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). Its central claim is a conceptual one: multidrug resistance should no longer be understood as the consequence of a single transporter’s overexpression, but as the output of converging transcriptional, metabolic, and stromal programs that together reduce intracellular drug accumulation and seed relapse.

At the heart of this reframing is the observation that transporter expression and activity are actively regulated by cellular stress. The authors highlight the integrated stress response, particularly the transcription factors ATF4 and JUN, as upstream drivers that can rapidly induce efflux competence when leukemic cells are exposed to chemotherapy or other environmental pressures. Work on stress-responsive enhancers in AML has shown that drug resistance can be induced dynamically—switched on within hours of treatment rather than emerging only through slow clonal selection. In this view, the transporter is the effector arm of a broader alarm system that leukemic cells deploy under duress.

The review also draws attention to stromal kinase signaling as a critical external input. Contact with mesenchymal stromal cells in the bone marrow activates pathways such as PKC–NF-κB, which in turn upregulate ABC transporter activity in leukemic blasts and stem cells. Studies cited in the review demonstrated that mesenchymal stromal cells can confer chemoresistance to myeloid leukemia blasts through activation of ABC transporters and so-called side population functionality—a flow-cytometric signature of high efflux capacity. In other words, the bone marrow niche itself behaves as a resistance-inducing microenvironment, teaching leukemic cells to defend themselves pharmacologically.

Metabolic reprogramming emerges as a third pillar of the network. The review describes an ABCC1–glutathione axis in which the antioxidant glutathione is conjugated to cytotoxic drugs and then exported by MRP1, linking redox homeostasis directly to efflux. Because glutathione metabolism is tightly coupled to cellular stress and mitochondrial function, metabolic shifts within leukemic stem cells can modulate transporter function without any change in transporter gene copy number. This provides a mechanistic explanation for why leukemic stem cells, which often rely on distinct metabolic programs compared with bulk blasts, are disproportionately enriched among chemotherapy-surviving populations.

The physical environment of the bone marrow adds further layers of regulation. Hypoxia within protective niches stabilizes HIF-1α, a transcription factor that the review identifies as a promoter of efflux competence and stem cell persistence. Lipid raft remodeling—changes in the organization of cholesterol-rich membrane microdomains—alters the trafficking and functional state of transporter proteins embedded in the plasma membrane. Meanwhile, extracellular vesicles provide a striking mechanism of resistance spread: earlier work showed that membrane microparticles can transfer functional P-glycoprotein from drug-resistant cells to drug-sensitive ones, effectively disseminating the resistance phenotype through the leukemic population. Leukemia-derived extracellular vesicles have also been shown to reprogram bone marrow mesenchymal stromal cells toward expression of poor-prognosis genes, closing the loop between tumor and niche.

Clinically, the stakes of this network-level view are substantial. Transcriptional profiling studies in AML cohorts have shown that ABC transporter expression predicts treatment failure, and co-expression of multiple transporters correlates with poor prognosis. In adult ALL, ABCB1 expression has been linked to measurable residual disease—a key marker of relapse risk. In CML, transporter-mediated cellular distribution of tyrosine kinase inhibitors such as imatinib contributes to resistance, with ABCB1 and ABCG2 lowering intracellular drug levels below therapeutic thresholds. The review also notes that transporter activity can undermine newer therapeutic classes: overexpression of ABCB1 and ABCG2 reduces the susceptibility of cancer cells to certain histone deacetylase inhibitors, and transporter expression may compromise responses to venetoclax-based regimens in subsets of patients.

The historical record of direct transporter inhibition, however, tempers enthusiasm for naive strategies. First- and second-generation P-glycoprotein inhibitors such as cyclosporine and zosuquidar produced disappointing clinical results in AML trials, largely because blocking the pump alone failed to account for the parallel survival pathways—anti-apoptotic signaling, stress adaptation, and niche protection—that leukemic cells maintain. The review argues that this failure was predictable from the network perspective: inhibiting one node of a redundant system simply redirects resistance through others.

Accordingly, the authors outline therapeutic strategies that target the regulatory networks surrounding transporters rather than the pumps in isolation. These include inhibiting stress pathways such as the integrated stress response and JUN/ATF4 signaling to prevent dynamic induction of efflux; disrupting stromal interactions, for instance by modulating CXCL12/CXCR4 axis signaling or targeting mesenchymal stromal cell plasticity, to remove niche-driven resistance cues; and metabolic interventions that deplete the glutathione-dependent export capacity of MRP1 or exploit vulnerabilities in leukemic stem cell metabolism. Combination approaches—pairing transporter-aware strategies with BH3-mimetic therapies such as venetoclax, or pairing MCL-1 inhibition with venetoclax—are presented as ways to simultaneously collapse multiple resistance arms.

The review also takes a methodological turn, evaluating standards for functional transporter assessment. It emphasizes inhibitor-controlled efflux assays, in which transporter activity is measured with and without specific inhibitors to distinguish true pump-mediated efflux from passive drug distribution or alternative mechanisms. The authors argue that inconsistent methodologies have muddied the literature, contributing to contradictory findings about transporter relevance across studies, and that standardized, inhibitor-controlled functional readouts should be a prerequisite for translational claims.

What emerges from the synthesis is a picture of minimal residual disease as a transporter-enabled, niche-protected state. Leukemic stem cells dwelling in hypoxic, stromal-rich bone marrow niches maintain high efflux capacity through a combination of transcriptional priming, metabolic provisioning, and microenvironmental instruction. Conventional chemotherapy depletes the bulk population, but these protected cells persist, forming the reservoir from which relapse springs. A durable therapeutic remission, the authors contend, will require interventions that are simultaneously transporter-aware and niche-adapted—drugs designed with the full resistance network in view rather than a single membrane protein.

The authors caution that much of the supporting evidence comes from cell-line models, patient-derived xenografts, and observational cohort studies, and that prospective clinical validation of network-targeted combinations remains ahead. Yet the conceptual shift they propose is already reshaping how researchers frame the problem. If multidrug resistance is a property of an integrated system—stress programs, stromal signaling, metabolism, vesicle communication, and membrane transport acting in concert—then the path to overcoming it lies in mapping that system’s vulnerabilities and attacking several nodes at once. For a disease like AML, where relapse remains the leading cause of treatment failure, that systems-level ambition may prove to be the review’s most consequential contribution.

Subject of Research: The role of ABC transporters (ABCB1/P-gp, ABCC1/MRP1, ABCG2/BCRP) in leukemia multidrug resistance and microenvironmental adaptation

Subject of Research: Cancer

Article Title: From pumps to networks: ABC transporters in leukemia resistance and microenvironmental adaptation

Article References: Jyotirmayee, Kumar, V., & Verma, M. (2026). From pumps to networks: ABC transporters in leukemia resistance and microenvironmental adaptation. Medical Oncology, 43(10), Article 274. https://doi.org/10.1007/s12032-026-03400-9

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03400-9

Keywords: ABC transporters, Multidrug resistance, Leukemia, Bone marrow microenvironment, Stress signaling, Leukemic stem cells, Efflux pumps, Glutathione, HIF-1α, Extracellular vesicles, Mesenchymal stromal cells, Chemoresistance

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Nathaniel Bowman. (September 11, 2026). ABC transporters drive leukemia drug resistance and microenvironmental adaptation. Scienmag. https://scienmag.com/abc-transporters-drive-leukemia-drug-resistance-and-microenvironmental-adaptation/

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