Crosstalk between AML and stromal cells triggers acetate secretion through the metabolic rewiring of stromal cells

Abstract

Acute myeloid leukaemia (AML) cells interact and modulate components of their surrounding microenvironment into their own benefit. Stromal cells have been shown to support AML survival and progression through various mechanisms. Nonetheless, whether AML cells could establish beneficial metabolic interactions with stromal cells is underexplored. By using a combination of human AML cell lines and AML patient samples together with mouse stromal cells and a MLL-AF9 mouse model, here we identify a novel metabolic crosstalk between AML and stromal cells where AML cells prompt stromal cells to secrete acetate for their own consumption to feed the tricarboxylic acid cycle (TCA) and lipid biosynthesis. By performing transcriptome analysis and tracer-based metabolic NMR analysis, we observe that stromal cells present a higher rate of glycolysis when co-cultured with AML cells. We also find that acetate in stromal cells is derived from pyruvate via chemical conversion under the influence of reactive oxygen species (ROS) following ROS transfer from AML to stromal cells via gap junctions. Overall, we present a unique metabolic communication between AML and stromal cells and propose two different molecular targets, ACSS2 and gap junctions, that could potentially be exploited for adjuvant therapy.

Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia

“…Our findings show that leukemia pre-exposure to HS-5 WT enhanced OCR compared to leukemia monocultures (KG1a, OCI-AML3, and K562) but preexposure to HS-5 ACSS2-KO abolished this observed enhanced metabolic or "respiratory" state. Recent studies describe increased acetate secretion and its incorporation into TCA and fatty acid synthesis in leukemia cocultures [53]. The results corroborate with our findings by a different approach that leukemia cells gain metabolic fitness.…”

“…Moreover, the compelling evidence on the role of ACSS2 in regulating the acetate levels through nuclear histone acetylation, fatty acids biosynthesis, and recycling of acyl groups when glucose or oxygen is deprived in cancer led us to further explore the role of ACSS2 in AML [44][45][46][47]51]. Evidence as to how acetate becomes available is just emerging [52][53][54] but if available, acetate in the form of acetyl coA can be used in energy production, lipid synthesis, and protein acetylation including histone acetylation [51] and possibly affecting the epigenetic response in AML [24]. We highlight herein that HDACi, Class I HDACs, promoted stroma-dependent protection possibly affecting nuclear acetate levels to support drug resistance in leukemia, a mechanism mirrored in bacterial acetyl coA synthetase (acs) by switching to acetate in developing antibiotic resistance [55].…”

Novel metabolomics-biohumoral biomarkers model for predicting survival of metastatic soft-tissue sarcomas

“…The acetate is a pivotal player in tumor metabolism. 27 , 28 , 29 Acetyl-coenzyme A (acetyl-CoA) is an active precursor of cellular lipid biosynthesis that under physiological conditions derives almost exclusively from glucose metabolism. Conversely, under metabolic stress conditions, as in neoplastic diseases, acetyl-CoA derives from acetate, reflecting the cancer cell metabolic reprogramming.…”

SSB-2548 Attenuates C-X-C chemokine receptor type 4 (CXCR-4) Activation to Induce Apoptosis; An in silico Guided invitro Validation in Acute Myeloid Leukemia cells

“…Many studies have established the role of CXCR-4 -SDF-1/CXCL12 in the "cross-talk" between leukemia cells and BM. The metabolic cross-talk of AML LSCs and BM stromal cells in the endosteal niche due to the high metabolic plasticity of AML cells help them to survive (reactive oxygen species) ROS-induced apoptosis [9][10][11]. This results in leukemia proliferation, extramedullary migration, in ltration, adhesion, and chemoresistance.…”