Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL

Abstract

Preleukemic clones carrying <i>BCR-ABL</i>^<i>p190</i> oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABL^p190 preleukemic state and show that limiting BCR-ABL^p190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABL^p190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABL^p190+<i>Pax5</i>^+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type <i>Pax5</i> allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (<i>IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1</i>) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first <i>in vivo</i> evidence that the combination between Sca1-BCR-ABL^p190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABL^p190 preleukemic cells.<b>Significance:</b> Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. <i>Cancer Res; 78(10); 2669-79. ©2018 AACR</i>.