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  • Loss of Pax5 confers the metabolic shift essential for the development of pB-ALL as a result of BCR-ABLp190 susceptibility
Loss of Pax5 confers the metabolic shift essential for the development of pB-ALL as a result of BCR-ABLp190 susceptibility

Loss of Pax5 confers the metabolic shift essential for the development of pB-ALL as a result of BCR-ABLp190 susceptibility

Ponente: Alberto Martín-Lorenzo

Centro de Investigación del Cáncer (CIC-IBMCC), laboratorio 13

Fecha: 04/05/2017 - 04/05/2017

Hora: 12:30

Salón de Actos del Centro de Investigación del Cáncer

A single driver is sufficient to promote precursor B-cell acute lymphoblastic leukemia (pB-ALL) formation in humans, but malignant progression requires additional genetic alterations. BCR-ABLp190 can be detected prenatally whereas BCR-ABLp190-pB-ALLs frequently exhibit additional PAX5 loss-of-function mutations as a second hit. However, the critical question of how PAX5 loss contributes to BCR-ABLp190 leukemogenesis on the basis of a preleukemic BCR-ABLp190 hematopoietic stem/progenitor cell (HS/PC) clone remains undefined. Here, we model a BCR-ABLp190 preleukemic state, showing that limiting BCR-ABLp190 expression to HS/PCs in mice (Sca1-BCR-ABLp190), causes pB-ALL at low penetrance, which resembles the human disease. These  pB-ALLs arise from BCR-ABLneg blast cells that are transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence and accumulations of genomic loss-of-function alterations in the remaining wild-type Pax5 allele. Mechanistically, we show that BCR-ABLneg/Pax5-deficient tumor pro-B cells exhibit a glycolytic switch resulting in elevated levels of glucose consumption, lactate production and ATP as well as an increased glycolytic activity and capacity. Our studies unveil the first in vivo evidence that the combination between BCR-ABLp190 susceptibility and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development.