Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells

The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia

“…This is in stark contrast to metabolic properties of healthy hematopoietic stem cells and bulk AML cells that show a far higher glycolytic reserve rendering them less sensitive to agents that inhibit mitochondrial activity ( 28 ). Metabolic plasticity of AML LSC nevertheless allows for an escape from metabolic pressure of venetoclax treatment by an increase in fatty acid oxidation (FAO) that continues to drive enhanced OxPhos when amino acid metabolism is inhibited leading to resistance to venetoclax/azacitidine treatment protocol ( 44 , 45 ), confirming previous experimental results that simultaneous pharmacological inhibition of FAO enhances sensitivity of AML cells to Bcl-2 inihibiton ( 46 ). Further support for the dependency of AML LSC on OxPhos has been lent by a recent report showing that chemoresistant AML LSC are better defined by their metabolic characteristics than their immunophenotype, with cytarabine resistant cells being highly dependent on OxPhos and FAO ( 47 ).…”

“…The group of patients that could most likely benefit from metabolic modulations are patients resistant to available therapies. As already mentioned, resistance to both cytarabine ( 47 )⁠ and venetoclax ( 44 , 45 )⁠ are mediated by increased OxPhos and metabolic switch to FAO, while resistance to FLT3 inhibitors is mediated through alterations in metabolism of glutamine ( 27 )⁠ and serine ( 26 ), as well as glycolysis ( 69 ). During intensive chemotherapy, AML cells appear to pass through a form of metabolic bottleneck producing resistant cells with a distinctive metabolic signature consisting of a switch in glutamine utilization primarily for nucleotide synthesis and gluthatione production and a modification of pyrimidine synthesis pathway to a higher dependency from extracellular aspartate provided by the bone marrow stroma ( 81 ).…”

CKS1-dependent proteostatic regulation has dual roles combating acute myeloid leukemia whilst protecting normal hematopoiesis

“…Here we provide evidence for CKS1 regulating RAC1/NADPH/ROS signalling (Figure 3H), a fundamental pathway involved in amplifying extrinsic and intrinsic signals in normal hematopoiesis and AML(4,44). The balance of intracellular ROS in normal and malignant hematopoietic cells has been of great interest in recent years(33,38), and changes in mitochondrial functions due to RAS mutations and nicotinamide-NAD metabolism underline the critical role for this pathway in primary patient resistance to Venetoclax(4,5). The induction of ROS in AML cell lines upon CKS1 inhibition, regardless of CKS1B expression, demonstrates that the balance of CKS1-dependent protein degradation is key to maintaining stress responses in AML.…”

“…With the average two-year survival rate as low as 5-15% in poor risk, older patients (>65yr), there is an unmet critical need for new therapeutic approaches(1). Recent developments, targeting the anti-apoptotic protein BCL2, has demonstrated that therapies affecting protein networks holds great promise for the poorest prognosis AMLs(2,3), yet resistance still emerges for a subset of patients through mitochondrial adaptions in residual leukemic cells(4,5).…”

MLL4 is a critical mediator of differentiation and ferroptosis in the epidermis

“…2A, Table 1). This was intriguing given that fatty acid metabolism has been implicated in promoting both metastasis and treatment resistance in cancer [28][29][30][31] . Notably, many of these significantly upregulated genes have been reported to be involved in driving cancer invasion and metastasis such as Acat (Soat1), Cd36, Fabp5, Mgll, Scd1, Slc1a5, and Slc7a11 32,33 .…”