IRAK1-regulated IFN-γ signaling induces MDSC to facilitate immune evasion in FGFR1-driven hematological malignancies

Abstract

Background Stem Cell leukemia/lymphoma syndrome (SCLL) presents as a myeloproliferative disease which can progress to acute myeloid leukemia and is associated with the coincident development of B-cell and T-cell lymphomas. SCLL is driven by the constitutive activation of fibroblast growth factor receptor-1 (FGFR1) as a result of chromosome translocations with poor outcome. Mouse models have been developed which faithfully recapitulate the human disease and have been used to characterize the molecular genetic events that are associated with development and progression of the disease. Methods CRISPR/Cas9 approaches were used to generate SCLL cells null for Interleukin receptor associated kinase 1 (IRAK1) and interferon gamma (IFNG) which were introduced into syngeneic hosts through tail vein injection. Development of the disease and changes in immune cell composition and activity were monitored using flow cytometry. Bead-based immunoassays were used to compare the cytokine and chemokine profiles of control and knock out (KO) cells. Antibody mediated, targeted depletion of T cell and MDSCs were performed to evaluate their role in antitumor immune responses. Results In SCLL, FGFR1 activation silences miR-146b-5p through DNMT1-mediated promoter methylation, which derepresses the downstream target IRAK1. IRAK1 KO SCLL cells were xenografted into immunocompetent syngeneic mice where the typical rapid progression of disease was lost and the mice remained disease free. IRAK1 in this system has no effect on cell cycle progression or apoptosis and robust growth of the KO cells in immunodeficient mice suggested an effect on immune surveillance. Depletion of T-cells in immunocompetent mice restored leukemogenesis of the KO cells, and tumor killing assays confirmed the role of T cells in tumor clearance. Analysis of the immune cell profile in mice transplanted with the IRAK1 expressing mock control (MC) cells shows that there is an increase in levels of myeloid-derived suppressor cells (MDSCs) with a concomitant decrease in CD4+/CD8+ T-cell levels. MDSC suppression assays and depletion experiments showed that these MDSCs were responsible for suppression of the T cell mediated leukemia cell elimination. Immuno-profiling of a panel of secreted cytokines and chemokines showed that activation of IFN-γ is specifically impaired in the KO cells. In vitro and in vivo expression assays and engraftment with interferon gamma receptor-1 (IFNGR1) null mice and IFNG KO SCLL cells, showed the leukemia cells produced IFN-γ directly participating in the induction of MDSCs to establish immune evasion. Inhibition of IRAK1 using pacritinib suppresses leukemogenesis with impaired induction of MDSCs and attenuated suppression of CD4+/CD8+ T-cells. Conclusions IRAK1 orchestrates a previously unknown FGFR1-directed immune escape mechanism in SCLL, through induction of MDSCs via regulation of IFN-γ signaling from leukemia cells, and targeting IRAK1 may provide a means of suppressing tumor growth in this syndrome by restoring immune surveillance.

A Cas9-fusion proximity-based approach generates anIrak1-Mecp2tandem duplication mouse model for the study of MeCP2 duplication syndrome

“…One factor likely contributing to the discrepancy between our findings and those identified in Mecp2 Tg3 mice may be the role of IRAK1, overexpressed at both transcript and protein level in the Mecp2 Dup mice, which is unaccounted for by previous models. IRAK1 signaling was previously shown to cause Th1 differentiation via induction of T-bet (Cai et al, 2021; Deng et al, 2003; Heiseke et al, 2015). Additionally, increased IRAK1 expression in the context of Behcet’s disease was associated with increased production of IFNγ (Sun et al, 2018).…”

Tumour‐derived exosomes promote the induction of monocytic myeloid‐derived suppressor cells from peripheral blood mononuclear cells by delivering miR‐106a‐5p and miR‐146a‐5p in multiple myeloma

“…Tumour‐secreted type I and II IFNs have promoted Tregs proliferation and expansion and PD‐L1 expression on tumour cells, promoting tumour progression in MM tumours 49,50 . Moreover, mounting evidence has focused on the association between IFN signalling and MDSC induction 51–53 . The underlying mechanism directing the opposite functions of IFN signalling is unknown; however, its immunosuppressive function is critical as a negative feedback force to protect the host from excessive immune stimulation.…”

“…49,50 Moreover, mounting evidence has focused on the association between IFN signalling and MDSC induction. [51][52][53] The underlying mechanism directing the opposite functions of IFN signalling is unknown; however, its immunosuppressive function is critical as a negative feedback force to protect the host from excessive immune stimulation.…”

Circular RNAs regulate parental gene expression: A new direction for molecular oncology research

“…Moreover, the binding sequence of circFECR1 to the FLI1 promoter contained abundant CpG islands. The further mechanistic studies found that circFECR1 could bind the promoter region of DNMT1 (DNA methyltransferase 1), a methyltransferase essential for maintaining DNA methylation, to downregulate DNMT1 transcription ( 57 ). The transcriptional regulatory capacity caused by DNA methylation was usually co-regulated by DNA methyltransferase and DNA demethylase, circFECR1 was also found to recruit the DNA demethylase TET1 (tet methylcytosine dioxygenase 1) in the promoter region of the host gene FLI1 to directly induce DNA demethylation of the parent gene, thereby regulating the transcriptional activity of the target gene FLI1 ( 58 ).…”