Abstract
Despite the high cure rates in childhood acute lymphoblastic leukemia (ALL), relapsed ALL remains a significant clinical problem. Genetic heterogeneity does not adequately explain variations in response to therapy. The chemoprotective tumor microenvironment may additionally contribute to disease recurrence. This study identifies metabolic reprogramming of leukemic cells by bone marrow stromal cells (BMSC) as a putative mechanism of drug resistance. In a BMSC-extracellular matrix culture model, BMSC produced chemoprotective soluble factors and facilitated the emergence of a reversible multidrug resistant phenotype in ALL cells. BMSC environment induced a mitochondrial calcium influx leading to increased reactive oxygen species (ROS) levels in ALL cells. In response to this oxidative stress, drug resistant cells underwent a redox adaptation process, characterized by a decrease in ROS levels and mitochondrial membrane potential with an upregulation of antioxidant production and MCL-1 expression. Similar expanded subpopulations of low ROS expressing and drug resistant cells were identified in pre-treatment bone marrow samples from ALL patients with slower response to therapy. This suggests that the bone marrow microenvironment induces a redox adaptation in ALL subclones that protects against cytotoxic stress and potentially gives rise to minimal residual disease. Targeting metabolic remodeling by inhibiting antioxidant production and antiapoptosis was able to overcome drug resistance. Thus metabolic plasticity in leukemic cell response to environmental factors contributes to chemoresistance and disease recurrence. Adjunctive strategies targeting such processes have the potential to overcome therapeutic failure in ALL.
Highlights
Modern chemotherapeutic regimens use ten or more different drugs over a 2–3 year period to treat childhood acute lymphoblastic leukemia (ALL)
bone marrow stromal cells (BMSC) were cultured on the plate till confluent, treated with Triton X-100 and NH4OH, washed with PBS to remove cellular components, only extracellular matrix (ECM) remained on the plate
Our study suggests that the BMSC microenvironment produces an oxidative stress response in ALL cells
Summary
Modern chemotherapeutic regimens use ten or more different drugs over a 2–3 year period to treat childhood ALL. Patients with high MRD levels have an increased risk of relapse [2] This suggests that MRD represents drug resistant subclones selected by specific chemotherapy schedules; MRD cells survive and proliferate over time giving rise to recurrence. We recently reported the superiority of mitoxantrone over idarubicin, in the context of a randomised clinical trial in patients with relapsed ALL [3] Both drugs were administered on the first two days of therapy but MRD levels after 4 weeks treatment were comparable in both arms, indicating that intrinsic drug resistance to idarubicin was not causal to outcome. Patients treated with mitoxantrone experienced a higher degree of myelosupression for up to 12 months after administration, suggesting that therapeutic benefit was related to an increased toxicity to the bone marrow, indicating the role of environment mediated drug resistance (EMDR) in tumor treatment failure [4, 5]
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