| First Author | Martín-Lorenzo A | Year | 2018 |
| Journal | Cancer Res | Volume | 78 |
| Issue | 10 | Pages | 2669-2679 |
| PubMed ID | 29490943 | Mgi Jnum | J:262298 |
| Mgi Id | MGI:6158977 | Doi | 10.1158/0008-5472.CAN-17-3262 |
| Citation | Martin-Lorenzo A, et al. (2018) Loss of Pax5 Exploits Sca1-BCR-ABL(p190) Susceptibility to Confer the Metabolic Shift Essential for pB-ALL. Cancer Res 78(10):2669-2679 |
| abstractText | Preleukemic clones carrying BCR-ABL(p190) 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)+Pax5(+/-) mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 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 (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo 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.Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669-79. (c)2018 AACR. |
