IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity

Abstract

The processes leading from disturbed B-cell development to adult B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remain poorly understood. Here, we describe Irf4−/− mice as prone to developing BCP-ALL with age. Irf4−/− preB-I cells exhibited impaired differentiation but enhanced proliferation in response to IL-7, along with reduced retention in the IL-7 providing bone marrow niche due to decreased CXCL12 responsiveness. Thus selected, preB-I cells acquired Jak3 mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to Jak3 mutants, devise a model to explain it, and describe structural and functional similarities to Jak2 mutations often occurring in human Ph-like ALL. Finally, targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4−/− leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. In this work, we present spontaneous leukemogenesis following IRF4 deficiency with potential implications for high-risk BCP-ALL in adult humans.

Puppet masters of B‐cell progenitor acute lymphoblastic leukemia: The preB cell receptor and the interleukin 7 receptor α

“…One interesting finding from the Irf4 –/– spontaneous leukemia mouse model is that fully transformed leukemia cells remained targetable through preBCR phase‐II signaling reinstation, achieved by forced IRF4 re‐expression in the cells: The IRF4 re‐expressing leukemia cells showed transcriptional signs of differentiation into small preB‐II cells before activating apoptosis [60]. Similarly, Blnk –/– BCR::ABL1 positive murine leukemia cells were targetable by reconstitution with BLNK.…”

“…While single deficiencies of both BLNK and IRF4 have been shown to be fully sufficient for spontaneous leukemogenesis [34,60], the respective double deficiencies markedly increase the likelihood of leukemogenesis (e.g., >75% at 16 weeks of age for BLNK/BTK double-deficient mice vs. <10% for BLNK singledeficient mice [33]; 50 days median survival for PU.1/IRF4 double-deficient mice vs. 130 days for PU.1 fl/+ Irf4 -/mice [50]).…”

“…This theory is supported by the fact that deficiency in JAK3 does not lead to B‐cell defects in humans [80]. Inversely, mouse B‐cell progenitors may primarily respond to IL‐7 and the IL‐7R linked to JAK3 [60].…”

“…Less obviously, cells can secure oncogenic IL-7 signaling also by acquiring primary or secondary JAK1 or JAK3 gain of function mutations, as those described in the spontaneous leukemia mouse models mentioned above [59,60,73]. For example, our group has shown that recurrent point mutations in the pseudokinase and kinase domains of Jak3 result in a heightened sensitivity toward IL-7, by acting downstream of the IL-7Rα chain [60]. We recently theorized that these mutations would lead to a weaker binding of the pseudokinase to the kinase domain within JAKs, thus disinhibiting signal transduction.…”

Childhood B-Cell Preleukemia Mouse Modeling

“…Similar to Pax5 +/− mice, Irf4 −/− mice also spontaneously develop B-ALL with incomplete penetrance (incidence 17.5%), when stressed with bacterial compounds (such as lipopolysaccharide (LPS), an important outer membrane component of gram-negative bacteria), due to the acquisition of Jak3 mutations [ 34 ]. Although the transformation process in Pax5 +/− B-ALL is independent of AID [ 30 ], in Irf4 − /− leukemias, AID might be playing a role in the acquisition of secondary mutations.…”