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Heme Is a Master Regulator of Gene Expression, Metabolism and Drug Sensitivity in Acute Myeloid Leukemia
Lev Kats1, Alexander Lewis1, Jessica Armstrong1, Fiona Brown2, Andrew Wei1,2, Kristin Brown1 and Emily Gruber1.1 Peter MacCallum Cancer Centre and The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
2 The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Acute myeloid leukaemia (AML) is an aggressive and deadly blood cancer and is the most common acute leukaemia in adults. Identification of metabolic pathways that are dysregulated in AML offers significant promise for the development of new therapeutic strategies. Heme is an iron containing porphyrin molecule that is produced de novo in most cell types. In addition to its catalytic role as a cofactor in hemoproteins, heme has diverse signalling functions including in kinase signalling cascades, chromatin remodelling and transcription. Despite the potential for heme to impact on various oncogenic processes, heme metabolism remains poorly characterised in most cancers including AML. Through integrated gene expression and metabolic analyses of mouse models, human AML cell lines and primary patient samples we found that leukaemic cells, and especially leukaemic stem cells, downregulate heme biosynthesis enzymes and are characterised by a low heme state. Reduced heme levels drive altered gene expression patterns, in part via the heme sensing transcription factor BACH1 which controls key stemness and metabolic genes including KIT, MEF2C, SLC7A11 and HK2. AML cells also demonstrate increased dependence on heme biosynthesis enzymes and are sensitive to pharmacological inhibition of ALAD and FECH. Pooled CRISPR screening unexpectedly revealed that heme starvation induces an unconventional form of programmed cell death in AML cells which depends on accumulation of lipoylated proteins. We also uncovered a host of hitherto unknown metabolic pathways that are synthetic lethal with de novo heme biosynthesis including glycolysis and sialic acid synthesis. Altogether, our data point to a model where low heme levels promote metabolic and transcriptional programs that are beneficial for self-renewal but also result in vulnerabilities that can be exploited for therapeutic benefit. Utilising our molecular and functional genomics data we designed a series of rational combination strategies for selective elimination of low heme cells that are being tested in vitro and in vivo.
This work is supported by a Perpetual IMPACT philanthropic grant and a fellowship from the Victorian Cancer Agency.
Speakers
Lev Kats