Deletion of 9p drives B-ALL through heterozygous inactivation of Pax5 and Cd72 in preleukemic cells
Belén Ruiz-Corzo, Ana Casado-García, Ninad Oak, Paula Somoza-Cotillas, Andrea López-Álvarez de Neyra, Jorge Martínez-Cano, Alba Pérez-Pons, Elena G. Sánchez, Oscar Blanco, Diego Alonso-López, Javier De Las Rivas, Susana Riesco, Pablo Prieto-Matos, Francisco Javier García Criado, María Begoña García Cenador, Alberto Orfao, Manuel Ramírez-Orellana, César Cobaleda, Carolina Vicente-Dueñas, Kim E. Nichols, Isidro Sánchez-García
Belén Ruiz-Corzo, Ana Casado-García, Ninad Oak, Paula Somoza-Cotillas, Andrea López-Álvarez de Neyra, Jorge Martínez-Cano, Alba Pérez-Pons, Elena G. Sánchez, Oscar Blanco, Diego Alonso-López, Javier De Las Rivas, Susana Riesco, Pablo Prieto-Matos, Francisco Javier García Criado, María Begoña García Cenador, Alberto Orfao, Manuel Ramírez-Orellana, César Cobaleda, Carolina Vicente-Dueñas, Kim E. Nichols, Isidro Sánchez-García
View: Text | PDF
Research Article Hematology Oncology

Deletion of 9p drives B-ALL through heterozygous inactivation of Pax5 and Cd72 in preleukemic cells

Abstract

The contribution of 9p deletion to B cell acute lymphoblastic leukemia (B-ALL) has remained elusive since its discovery more than 40 years ago. Here we show that loss of CD72 is recurrent in B-ALL cases containing PAX5 deletions, and that Cd72 haploinsufficiency drives B-ALL development in Pax5+/– mice. Mechanistically, Cd72+/–;Pax5+/– precursor B cells exhibited an inflammatory transcriptional profile characterized by a decrease in Myd88 expression, a finding that aligns with our previous studies of B-ALL development in Pax5+/– mice following exposure to immune stressors. These combined genomic analyses and functional models provide compelling evidence that co-deletion of 2 contiguous genes, Pax5 and Cd72, drives B cell leukemogenesis.

Authors

Belén Ruiz-Corzo, Ana Casado-García, Ninad Oak, Paula Somoza-Cotillas, Andrea López-Álvarez de Neyra, Jorge Martínez-Cano, Alba Pérez-Pons, Elena G. Sánchez, Oscar Blanco, Diego Alonso-López, Javier De Las Rivas, Susana Riesco, Pablo Prieto-Matos, Francisco Javier García Criado, María Begoña García Cenador, Alberto Orfao, Manuel Ramírez-Orellana, César Cobaleda, Carolina Vicente-Dueñas, Kim E. Nichols, Isidro Sánchez-García

×

Figure 5

Pathways transcriptionally enriched in preleukemic CD72+/–;Pax5+/– and Pax5+/– cells.

Options: View larger image (or click on image) Download as PowerPoint
Pathways transcriptionally enriched in preleukemic CD72+/–;Pax5+/– and P...
GSEA of Hallmark pathways comparing CD72+/–;Pax5+/– and WT pro-B cells (A) or Pax5+/– and WT pro-B cells (B). Bar plot displays the normalized enrichment scores (NES) for significantly enriched Hallmark gene sets, comparing the 2 experimental conditions indicated in each case. Gene sets with positive NES values (right side) are enriched in the CD72+/–;Pax5+/– or the Pax5+/– group, while those with negative NES values (left side) are enriched in the WT group. The bars are color coded according to the false discovery rate (FDR) q values, with more significant gene sets shown in red and less significant ones in blue, as indicated by the color gradient legend. Only pathways with FDR q values below the significance threshold are shown (q < 0.05). (C) CD72 heterozygosity promotes Myd88 downregulation in CD72+/–;Pax5+/– pro-B cells. Myd88 mRNA expression was quantified by qPCR in cultured CD72+/–;Pax5+/– (n = 4) and Pax5+/– (n = 4) pro-B cells. Total bone marrow from Myd88−/− mice was included as a negative control, and bone marrow pro-B cells from WT mice (n = 3) were used as a reference. Each dot represents an individual sample, and bars indicate the mean ± SEM. Data were analyzed by 1-way ANOVA (***P < 0.0001) followed by Dunnett’s multiple-comparison test versus the control group (WT pro-B cells), and multiplicity-adjusted P values are reported.