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

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 2

Genetic changes in B-ALL blasts from Cd72+/–;Pax5+/– mice.

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Genetic changes in B-ALL blasts from Cd72+/–;Pax5+/– mice. (A) Whole-gen...
(A) Whole-genome sequencing (WGS) of leukemic blasts from Cd72+/–;Pax5+/– mice. Oncoprint summarizing somatic single nucleotide variants (SNVs) and copy number alterations across 15 leukemia samples from Cd72+/–;Pax5+/– mice. Alterations are grouped by gene. Tumor DNA was extracted from whole leukemic bone marrow, with matched tail DNA serving as the germline reference. Known hotspot mutations previously reported in human or mouse leukemia are highlighted in red. The mean variant allele frequency (VAF) for each SNV is displayed in the dot plot to the right. (B) Visualization of somatic alterations in leukemic Pax5+/–;Cd72+/– mice. No somatic Cd72 alterations were found in all the Pax5+/–;Cd72+/– mice analyzed by WGS, except the germline deletion for first 4 exons as expected. G, germline DNA; T, tumor DNA.