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BCAT1 is a novel target of MLL fusions and essential for leukemic stem cell transformation

Schmid, Theresa

[thumbnail of Thesis_Final_without_TS.pdf] PDF, English
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In cancer, the branched-chain amino acid (BCAA) metabolism is frequently activated through the increased uptake (second only to glutamine) of valine, leucine, and isoleucine (Jain et al., 2012), as well as the overexpression of branched-chain amino acid transaminase 1 (BCAT1), the cytoplasmic BCAA transaminase. We and others showed that proliferation, migration, and chemoresistance of a variety of cancer entities, such as glioblastoma, breast cancer, and myeloid leukemia, are heavily reliant on BCAT1 expression (Hattori et al., 2017; Raffel et al., 2017; Thewes et al., 2017; Tönjes et al., 2013). Epigenetic gene regulation and metabolism are highly intertwined, as many histone and DNA modifiers rely on substrates and cofactors provided by various metabolic reactions. For example, in cancer, the upregulation of BCAT1 results in a decrease of α-KG and a reduced activity of α-KG dependent enzymes, such as EGLN1 (Raffel et al., 2017). Furthermore, DNA hypermethylation is observed upon BCAT1 suppression in acute myeloid leukemia (AML), suggesting an α-KG-dependent effect on the TET-family DNA demethylases (Raffel et al., 2017). In an attempt to unravel the interdependencies of BCAT1 and chromatin-modifying enzymes, I discovered that the upregulation of BCAT1 in mammary carcinoma xenografts influences histone modifications in an α-KG-independent manner. Global upregulation of gene expression mediated by altered chromatin modifications in BCAT1 knockdown breast cancer xenografts led to a comparison between BCAT1 and histone modifiers in expression data sets of breast cancer and AML patients. H3K4 methyltransferase MLL was found to be the most significantly positively correlating modifier in both cancer entities. MLL has been extensively studied in leukemia in which recurring translocations lead to gain-of-function rearrangements, such as MLL-AF9 and MLL-ENL fusion. These oncogenic fusions are driver gene mutations, and I was able to identify BCAT1 as one of their targets regulating its expression. MLL-AF9 and MLL-ENL were able to transform hematopoietic stem and progenitor cells (HSPCs) into leukemic stem cells (LSCs). However, loss of Bcat1 or its transaminase activity results in loss of self-renewal and immortalization, making Bcat1 activity essential for MLL fusion-mediated tumor development. Further expression and histone modification profiling of transformed wildtype HSPCs, as well as Bcat1 knockout HSPCs and their rescues, revealed that the lack of Bcat1 initiates the inhibition of DNA replication and cell cycle arrest missing in Bcat1 wildtype cells. BCAT1s limited expression in most healthy tissues makes it an interesting target for cancer therapy. Furthermore, this and other studies implicate that the inhibition of BCAT1’s transaminase activity can eradicate LSCs and may prevent relapse. Additionally, controlling BCAT1 has the potential to reduce tumor development, relevant especially for patients harboring clonal hematopoiesis of intermediate potential (CHIP).

Document type: Dissertation
Supervisor: Klingmüller, Prof. Dr. Ursula
Place of Publication: Heidelberg
Date of thesis defense: 15 December 2021
Date Deposited: 14 Jun 2022 12:48
Date: 2023
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
DDC-classification: 570 Life sciences
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