IFN‐γ directly inhibits murine B‐cell precursor leukemia‐initiating cell proliferation early in life

Abstract

The early-life immune environment has been implicated as a modulator of acute lymphoblastic leukemia (ALL) development in children, with infection being associated with significant changes in ALL risk. Furthermore, polymorphisms in several cytokine genes, including IL-10 and IFN-γ, are associated with leukemia development. However, the mechanisms and timing of these influences remain unknown. Here, we use the Eμ-ret transgenic mouse model of B-cell precursor ALL to assess the influence of IFN-γ on the early-life burden of leukemia-initiating cells. The absence of IFN-γ activity resulted in greater numbers of leukemia-initiating cells early in life and was associated with accelerated leukemia onset. The leukemia-initiating cells from IFN-γ-knockout mice had reduced suppressor of cytokine signaling (SOCS-1) expression, were significantly more sensitive to IFN-γ, and exhibited more rapid expansion in vivo than their wild-type counterparts. However, sensitivity to this inhibitory pathway was lost in fully transformed IFN-γ-knockout leukemia cells. These results demonstrate that the influence of IFN-γ on ALL progression may not be mediated by selection of nascent transformed cells but rather through a general SOCS-mediated reduction in B-cell precursor proliferation. Thus, while cytokine levels may influence leukemia at multiple points during disease progression, our study indicates a significant early influence of basal, infection-independent cytokine production on leukemogenesis.

Gene Expression and Survival of Acute Lymphoblastic Leukemia Cells After Allogeneic Transplant

“…There is a literature on the impact of inflammatory cytokines on hematopoiesis that shows interferon-gamma inhibits normal hematopoiesis (43). There is conflicting literature on the effect on malignant B cells with some reports showing impairment (44) others showing growth enhancement (45). Our data suggest that in the setting of allogeneic transplant the net effect is impairment of malignant B cell survival with both the cytokines and cyclosporine contributing to leukemia cell death.…”

“…The mechanisms for the graft versus leukemia are not fully known. Much of the literature has focused on T cell and NK cell antileukemia cytolytic activity, although some studies have pointed to a role for interferon gamma (44,(47)(48)(49). In our system, we asked the question of whether the changes in ALLs induced by the cytokines and cyclosporine would change their sensitivity to allogeneic cytolytic cells.…”

Myeloid cell‐based delivery of IFN‐γ reprograms the leukemia microenvironment and induces anti‐tumoral immune responses

“…We observed that IFN‐γ causes early proliferation impairment, as a direct effect on B‐ALL cells, in addition to immune‐mediated effects on the more immunogenic subclones (Fidanza et al , 2017). This “equilibrium phase” is followed by an “escape phase” where less immunogenic and more aggressive B‐ALL subpopulations are selected.…”

Bone Marrow Soluble Immunological Mediators as Clinical Prognosis Biomarkers in B-Cell Acute Lymphoblastic Leukemia Patients Undergoing Induction Therapy

“…The analysis of biomarker signatures further supports these findings ( Figures 2 and 5 ). It has been proposed that while cytokine levels may influence leukemia progression at multiple time points during disease development, other studies have suggested a relevant early influence of basal cytokine production on leukemogenesis ( 22 ). Nevertheless, studies of chemokines and cytokines in B-ALL that focus on prognostic markers are still scarce.…”

“…Nevertheless, studies of chemokines and cytokines in B-ALL that focus on prognostic markers are still scarce. Research using murine models have demonstrated that the absence of IFN-γ results in higher numbers of leukemia-initiating cells and accelerated leukemia onset ( 22 ).…”