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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
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Research Article Hematology Oncology

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

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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

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Figure 4

CD72+/–;Pax5+/– preleukemic cells are distinct from Pax5+/– or WT pro-B cells.

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CD72+/–;Pax5+/– preleukemic cells are distinct from Pax5+/– or WT pro-B...
(A) GSEA comparing Cd72+/–;Pax5+/– and Pax5+/– preleukemic pro-B cells in order to identify potential signatures of gene expression associated with different biological processes. The bar plot displays the normalized enrichment scores (NES) for Hallmark gene sets significantly enriched between the 2 cell populations. Positive NES values (right side) indicate gene sets enriched in Cd72+/–;Pax5+/– cells, while negative NES values (left side) indicate gene sets enriched in Pax5+/– cells. Bars are colored by the false discovery rate (FDR) q value, with the most statistically significant gene sets shown in red and less significant in blue, as indicated by the gradient scale. Cd72+/–;Pax5+/– cells exhibit strong enrichment for proliferative and metabolic pathways such as MYC, E2F, p53, and MTORC1. In contrast, Pax5+/– cells are enriched for pathways associated with immune signaling, differentiation, and stress responses, including complement system, IL-2/STAT5 signaling, epithelial-mesenchymal transition, and hypoxia hallmarks. Only gene sets with q values of less than 0.01 are displayed. These findings suggest distinct transcriptional programs underpin the biological differences between Cd72+/–;Pax5+/– and Pax5+/– populations. (B–D) Transcriptomic analysis of the indicated genotypes shows genes that were significantly induced or repressed within preleukemic B cells (bone marrow B220+ cells) of CD72+/–; Pax5+/– (B and C) and Pax5+/– (D) mice compared with Pax5+/– or WT cells. This was determined using significance analysis of microarrays with an |FC| of greater than 2 and P value of less than 0.05. Each row represents a separate gene, and each column denotes a separate mRNA sample. The level of expression of each gene in each sample is represented using a red–blue color scale (upregulated genes are displayed in red and downregulated genes in blue).

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