A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia–like syndrome in BXH-2 mice

Abstract

BXH-2 mice develop a fatal myeloid leukemia by a two-step mutagenic process. First, a BXH-2–specific recessive mutation causes a myeloproliferative syndrome. Second, retroviral insertions alter oncogenes or tumor suppressors, resulting in clonal expansion of leukemic cells. We have identified a recessive locus on chromosome 8 (Myls) that is responsible for myeloproliferation in BXH-2. This Myls interval has been narrowed down to 2 Mb and found to contain several positional candidates, including the interferon consensus sequence–binding protein 1 gene (Icsbp, also known as interferon regulatory factor 8 [IRF8]). We show that BXH-2 mice carry a mutation (915 C to T) resulting in an arginine-to-cysteine substitution at position 294 within the predicted IRF association domain of the protein. Although expression of Icsbp1 mRNA transcripts is normal in BXH-2 splenocytes, these cells are unable to produce interleukin 12 and interferon-γ in response to activating stimuli, confirming that R294C behaves as a loss-of-function mutation. Myeloproliferation in BXH-2 mice is concomitant to increased susceptibility to Mycobacterium bovis (BCG) despite the presence of resistance alleles at the Nramp1 locus. These results suggest a two-step model for chronic myeloid leukemia in BXH-2, in which inactivation of Icsbp1 predisposes to myeloproliferation and immunodeficiency. This event is required for retroviral replication, and subsequent insertional mutagenesis that causes leukemia in BXH-2 mice.

Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells

“…Indeed, myeloid cells from IRF-8-deficient mice exhibit reduced spontaneous apoptosis and a significant decrease in apoptosis induced by DNA damage (54). Furthermore, IRF-8-deficient mice develop nonrapid leukemia suggesting that additional events lead to the leukemic phenotype (12,55). In addition, as shown here, macrophages and dendritic cells extracted from IRF-8 Ϫ/Ϫ mice exhibit low levels of basal PML expression that could not be induced with IFN-␥.…”

The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation

“…Mouse strains carrying complete (Irf8 −/− ) or severe (Irf8 m/m ; BXH2) loss-offunction alleles at Irf8 either lack all DC subsets (Irf8 −/− ) or lack CD8α + conventional DCs (BXH2; Aliberti et al, 2003;Turcotte et al, 2005). Moreover, Irf8 mutant mice develop a chronic myelogenous leukemia-like syndrome characterized by the expansion of immature granulocytes (Holtschke et al, 1996;Turcotte et al, 2004).…”

ICSBP promoter methylation in myelodysplastic syndromes and acute myeloid leukaemia

“…1,2 Later, ICSBP-deficient mice were shown to develop a disease resembling human chronic myeloid leukaemia, 3,4 suggesting a tumour suppressor function of ICSBP. ICSBP functions as a molecular switch factor directing the differentiation of bi-potential myeloid precursors toward the monocytic lineage, 5 possibly by forming heterodimeric complexes with PU.1.…”

“…Hypomethylating agents are active in those patients. 4,5 In particular, azacitidine (AZA) has demonstrated a survival benefit over conventional care regimens in higher risk MDS (including AML with 20-30% blasts) 6 and has become the standard of care in those patients (at least for those not eligible for allogeneic stem cell transplantation). Studies of MK in AML have been conducted in patients receiving intensive chemotherapy.…”