Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5 -Inherited Susceptibility

• Published in: Cancer discovery Vol. 5; no. 12; pp. 1328 - 1343
• Main Authors: Martín-Lorenzo, Alberto, Hauer, Julia, Vicente-Dueñas, Carolina, Auer, Franziska, González-Herrero, Inés, García-Ramírez, Idoia, Ginzel, Sebastian, Thiele, Ralf, Constantinescu, Stefan N., Bartenhagen, Christoph, Dugas, Martin, Gombert, Michael, Schäfer, Daniel, Blanco, Oscar, Mayado, Andrea, Orfao, Alberto, Alonso-López, Diego, Rivas, Javier De Las, Cobaleda, César, García-Cenador, Maria Begoña, García-Criado, Francisco Javier, Sánchez-García, Isidro, Borkhardt, Arndt
• Format: Journal Article
• Language: English
• Published: United States 01.12.2015
• Subjects: Animals; Bone Marrow Transplantation; Cell Line, Tumor; Cell Transformation, Neoplastic; Cluster Analysis; Disease Models, Animal; Disease Susceptibility; Drug Resistance, Neoplasm - genetics; Exome; Female; Gene Expression Profiling; Genotype; High-Throughput Nucleotide Sequencing; Host-Pathogen Interactions; Interleukin-7 - metabolism; Interleukin-7 - pharmacology; Janus Kinase 3 - antagonists & inhibitors; Janus Kinase 3 - genetics; Male; Mice; Mice, Knockout; Mutation; PAX5 Transcription Factor - genetics; Phenotype; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - etiology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Protein Kinase Inhibitors - pharmacology; Receptors, Interleukin-7 - genetics; STAT5 Transcription Factor - genetics; Virus Integration
• ISSN: 2159-8274; 2159-8290; 2159-8290
• DOI: 10.1158/2159-8290.CD-15-0892

Earlier in the past century, infections were regarded as the most likely cause of childhood B-cell precursor acute lymphoblastic leukemia (pB-ALL). However, there is a lack of relevant biologic evidence supporting this hypothesis. We present in vivo genetic evidence mechanistically connecting inherited susceptibility to pB-ALL and postnatal infections by showing that pB-ALL was initiated in Pax5 heterozygous mice only when they were exposed to common pathogens. Strikingly, these murine pB-ALLs closely resemble the human disease. Tumor exome sequencing revealed activating somatic, nonsynonymous mutations of Jak3 as a second hit. Transplantation experiments and deep sequencing suggest that inactivating mutations in Pax5 promote leukemogenesis by creating an aberrant progenitor compartment that is susceptible to malignant transformation through accumulation of secondary Jak3 mutations. Thus, treatment of Pax5+/− leukemic cells with specific JAK1/3 inhibitors resulted in increased apoptosis. These results uncover the causal role of infection in pB-ALL development. Significance: These results demonstrate that delayed infection exposure is a causal factor in pB-ALL. Therefore, these findings have critical implications for the understanding of the pathogenesis of leukemia and for the development of novel therapies for this disease. Cancer Discov; 5(12); 1328–43. ©2015 AACR. See related commentary by Greaves and Müschen, p. 1244. This article is highlighted in the In This Issue feature, p. 1225