Infection Exposure Is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result ofPax5-Inherited Susceptibility

Abstract

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 specifi c 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 fi ndings 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.

Infection Exposure PromotesETV6-RUNX1Precursor B-cell Leukemia via Impaired H3K4 Demethylases

“…However, we did not find this high proportion of differentially regulated epigenetic regulator genes in a related Pax5 þ/À model of pB-ALL (Table 2 and Supplementary Table S5; ref. 46). These data indicate that ETV6-RUNX1 specifically regulates transcription of histone modifying genes of the KDM family and support a specific role of histone modification in preleukemic ETV6-RUNX1 cells (Supplementary Table S5).…”

“…We previously proved the infectious hypothesis stated by Ward in 1917 in a murine model of Pax5 haploinsufficiency (46), which can now be extended to the commonest subtype of childhood leukemia. It is of much broader interest for our general understanding of leukemia development to know if the very common ETV6-RUNX1 fusion acts cooperatively with infection.…”

Chronic lymphocytic leukemia: Time to go past genomics?

“…One example of this latter category could be PAX5 mutations. Based on murine models, PAX5 impairment may not significantly affect hematopoietic differentiation, but in cooperation with immune stimuli may facilitate acute B-cell transformation [124]. Finally, it remains to be determined whether mutations would be specific for the third step.…”

“…PAX5 locks B-cell differentiation as PAX5-deficient cells are able to trans-differentiate in T and myeloid cells [122,123]. Furthermore Pax5 heterozygous mice show an accumulation of IL7-dependant proB cells and develop B-ALL when challenged by infections [124]. Translocations and mutations involving PAX5 have been observed in B-cell lymphomas [125] and B-ALL [126].…”

A germ-line deletion of APOBEC3B does not contribute to subtype-specific childhood acute lymphoblastic leukemia etiology

“…Experimental studies in mice have shown that PAX5 mutation, a predisposing risk factor in some childhood ALL cases, can result in development of ALL following exposure to common infection. 17 Though there is no apparent relationship between the germline APOBEC3B deletion polymorphism and ALL risk, delineating a potential role for the polymorphism in tumor progression may have treatment implications, warranting further study.…”