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 1

Pax5 and Cd72 heterozygosity cooperate in driving B-ALL.

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Pax5 and Cd72 heterozygosity cooperate in driving B-ALL. (A) Localizati...
(A) Localization of PAX5, CD72, and CDKN2A on human chromosome 9. PAX5 and CDKN2A are frequently deleted in human B-ALL. Created with BioRender. (B) B-ALL–specific survival curve of Cd72+/–;Pax5+/– mice maintained in a specific pathogen–free (SPF) facility (red, n = 54), compared with Pax5+/– maintained in a conventional facility (CF) (blue, n = 41; P = 0.1137), Pax5+/– mice maintained in an SPF facility (black, n = 15; **P = 0.0083), and Cd72+/– mice maintained in an SPF facility (green, n = 14; *P = 0.0120) mice. Differences in Kaplan-Meier survival plots of transgenic and WT mice were analyzed using the log-rank (Mantel-Cox) test. (C) Flow cytometric analysis of the bone marrow and peripheral blood of a Cd72+/–;Pax5+/– (B834) mouse with leukemia. Representative plots of cell subsets are shown, alongside comparisons with healthy Cd72+/– (B924) and Pax5+/– (S907) mice. (D) Splenic H&E staining of Cd72+/–;Pax5+/– (A120) leukemic mouse shows infiltration of blast cells in spleen. Loss of normal architecture due to infiltrating leukemic cells can be seen. Tissues from a control littermate WT mouse are shown for reference. Scale bars: 100 μm (top) and 50 μm (bottom). (E) PCR analysis of immunoglobulin heavy-chain gene rearrangements in leukemia-infiltrated bone marrow (BM) and lymph nodes (LNs) of Cd72+/–;Pax5+/– mice with the disease (n = 5). Thymocytes (T cells) were included as a negative control, and sorted CD19+ B cells (B cells) from the spleens of healthy mice were included as a positive control for polyclonal rearrangements within the mature B cell population (indicated by numbers 1–8).