Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

Abstract

Switzerland 2 TRANSAUTOPHAGY: European network for multidisciplinary research and translation of autophagy knowledge, COST Action CA15138 Abstract Acute myeloid leukemia (AML) is a blood cancer characterized by a block in differentiation and increased survival of the resulting AML blast cells. While standard chemotherapy for AML cures only 30% of patients, differentiation-inducing therapy using all-trans retinoic acid (ATRA) in combination with arsenic trioxide achieves 90% cure rates in acute promyelocytic leukemia (APL). A better understanding of the molecular mechanisms underlying ATRA therapy in APL may provide new perspectives in the treatment of additional AML subtypes.Fatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis. While FASN levels are very low in healthy adult tissues, it is often highly expressed in cancer cells, thus representing a potential therapeutic target. We found that FASN mRNA levels were significantly higher in AML patients than in healthy granulocytes or CD34 + hematopoietic progenitors in two AML cohorts (n=68, n=203) (p<0.05). Accordingly, FASN levels decreased during ATRA-mediated granulocytic differentiation of APL cells, partially via autophagic degradation. Furthermore, our data suggests that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG), accelerates the differentiation of APL cell lines and significantly resensitized ATRA refractory non-APL AML cells. Decreasing FASN expression reduced mTOR activity and promoted translocation of transcription factor EB (TFEB) to the nucleus. Lysosomal biogenesis was activated, consistent with TFEB transcriptional activation of CLEAR network genes.Together, our data demonstrates that inhibiting FASN expression in combination with ATRA treatment promotes granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells. BioRXiv

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“…TFEB is a key transcriptional regulator of more than 500 genes comprising the CLEAR (Coordinated Lysosomal Expression and Regulation) network of autophagy and lysosomal genes. FASN inhibition is shown to promote TFEB nucleus translocation and enhance lysosome biogenesis [38].…”

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“…It is required for AML cell proliferation and was shown to be low in normal HSCs derived from healthy donors and highly overexpressed in AML patients. Inhibition of FASN with RNAi or epigallocatechin-3-gallate accelerated granulocytic differentiation in acute promyelocytic leukaemia cells and re-sensitised them to ATRA treatment ( 89 ). This process was suggested to be mediated through lysosomal biogenesis and autophagy ( 89 ).…”