Role of branched-chain amino catabolism in lymphopoiesis and lymphomagenesis

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant) Cancer cells rewire metabolic pathways to drive the uptake and/or catabolism of nutrients that sustain the high energetic demands needed for their growth (mass) and rapid rates of proliferation. Myc oncoproteins function as transcription factors and are activated in over half of all human cancers. Myc induces the transcription of several genes involved in glycolysis and glutaminolysis, including those encoding transporters of glucose, glutamine, lactate and branched-chain amino acids (BCAA: valine, leucine and isoleucine, via LAT1/SLC7A5). Tumors driven by Myc are addicted to and utilize L-glutamine to feed carbon intermediates into the Krebs cycle. We reasoned that Myc would also control the catabolism of BCAAs, which also provides key metabolic intermediates, specifically acetoacetate, acetyl-CoA, propionyl-CoA/succinyl-CoA, NADH and FADH2. In support of this notion, our new studies of Eμ-Myc transgenic mice, a validated model of human B cell Burkitt lymphoma (BL) that bear MYC/Ig translocations, and of BL cells, demonstrate that: (i) premalignant and neoplastic Myc-expressing B cells express elevated mRNA and protein levels of Bcat1, which is a bona fide Myc transcription target and the first enzyme in BCAA catabolism; (ii) elevated levels of several other enzymes that direct BCAA catabolism are evident in Eμ-Myc B cells and BL; (iii) BCAT1 knockdown impairs the growth, survival and clonogenicity of BL cells; (iv) treatment with Gabapentin, a known BCAT1 inhibitor, impairs the growth and survival of Eμ-Myc lymphoma and of BL, but not of normal B cells. These findings support the hypothesis that BCAT1 is necessary for the development and maintenance of Myc-driven lymphoma. In Specific Aim 1, we will use mouse models to test if Bcat1 plays essential, intrinsic roles in B lymphopoiesis and homeostasis, and if Bcat1 loss affects B cell proliferation and survival. In Specific Aim 2, we will test if Bcat1 is necessary for the development and maintenance of Myc-driven lymphomagenesis. Here we will assess the effects of Bcat1 loss: (i) on the proliferation and survival of pre-malignant Eμ-Myc B cells; (ii) on lymphoma onset and overall survival; and (iii) on maintenance of the malignant state. In Specific Aim 3, we will defin the metabolic perturbations that ensue following chronic versus acute Bcat1 loss or depletion in normal B cells, Eμ-Myc lymphomas and BL cell lines. Here we will assess changes in the steady-state levels and flux of metabolites derived from BCAAs, and possible alterations in mitochondrial respiration, glycolysis and nutrient uptake. In addition, the effects of Bcat1 loss o depletion on the sensitivity of mouse and human lymphomas to glycolytic, OXPHOS and lactate transport inhibitors will be determined. We submit that these studies will establish BCAA catabolism as a novel therapeutic vulnerability for human tumors with MYC/MYCN involvement and that they will offer new avenues for cancer prevention and treatment.