Mitochondrial Dysfunction Fuels Drug Resistance in Adult T-cell Acute Lymphoblastic Leukemia

Following our previous work indicating that a decreased mitochondrial activity is an important feature of tumour aggressiveness in adult T-ALL, we assembled the largest known tumour bank, consisting of 133 samples, to uncover the underlying mechanism. Transcriptomic analysis of these tumours showed that down-regulation of mitochondrial activity plays a central role in mediating the activation of ABCB1, a gene associated with multidrug resistance. Furthermore, our research identified de novo lipid synthesis and lipid accumulation as key mechanisms facilitating ABCB1 activation in T-ALL. Lipid accumulation, together with down-regulation of β-oxidation, promote the activation of lipogenic transcription factors, LXRs, which are the strong drivers of ABCB1 gene activation. This knowledge not only allows us to better understand the biology of aggressive T-ALL, but also to shed light on the mechanisms underlying tumour resistance to induction chemotherapy. We propose that in patients with tumours exhibiting low mitochondrial activity, the inhibition of de novo lipogenesis and restriction of dietary fats, such as caprylic acid, could mitigate the treatment resistance. Bone marrow (BM) samples containing high percentages of leukemic blasts from newly-diagnosed adult T-ALL patients were collected at the Hematology Department of Ruijin hospital, Shanghai Jiaotong university school of medicine. Diagnoses were assigned based on the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasm and NCCN Guidelines Version 2.2024-Acute Lymphoblastic Leukemia