Immunodeficiency and Chronic Myelogenous Leukemia-like Syndrome in Mice with a Targeted Mutation of the ICSBP Gene

Abstract

Interferon consensus sequence binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Mice with a null mutation of ICSBP exhibit two prominent phenotypes related to previously described activities of the IRF family. The first is enhanced susceptibility to virus infections associated with impaired production of IFN(gamma). The second is deregulated hematopoiesis in both ICSBP-/- and ICSBP+/- mice that manifests as a syndrome similar to human chronic myelogenous leukemia. The chronic period of the disease progresses to a fatal blast crisis characterized by a clonal expansion of undifferentiated cells. Normal mice injected with cells from mice in blast crisis developed acute leukemia within 6 weeks of transfer. These results suggest a novel role for ICSBP in regulating the proliferation and differentiation of hematopoietic progenitor cells.

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.…”

“…Monosomal karyotype (MK) has been defined by Breems et al 2 in acute myeloid leukemia (AML) as the presence of at least two autosomal monosomies or of a single monosomy associated to at least one structural abnormality. 3 In the report by Patnaik et al in MDS, 83% of complex karyotypes (defined according to the international prognostic scoring system (IPSS) criteria as the presence of three or more independent chromosomal aberrations) were monosomal, and those patients had indeed poorer prognosis, in terms of overall (OS) and progression-free survival, than other MDS with complex karyotype. Presence of monosomy 5 (À5) or 7 (À7) did not add further prognostic value to MK; del 5q and del 7q were not considered in that analysis.…”

“…Studies of MK in AML have been conducted in patients receiving intensive chemotherapy. 2,3 The MDS study of Patnaik et al 1 included patients analyzed between 1990 and 2010, and thus probably only a fraction of those patients had received hypomethylating agents. We thought useful to review the prognostic value of MK in higher risk MDS treated with AZA.…”

Acceleration of chronic myeloproliferation by enforced expression of Meis1 or Meis3 in Icsbp-deficient bone marrow cells

“…As Meis1 and Meis3 further enhance granulopoiesis in Icsbp-deficient but not wild-type mice, we investigated the expression of Meis family members in BM myeloid precursor populations and peripheral granulocytes of C57BL/6 (Icsbp þ / þ ), Icsbp þ /À and Icsbp À/À mice by real-time reverse transcription-PCR. As Icsbp À/À mice produce mRNA carrying the nonsense mutation, it is possible to detect Icsbp mRNA in these mice (Holtschke et al, 1996). Gene expression of Meis1a, Meis1b (an alternative splicing form of Meis1 gene) and Meis3 mRNAs was enhanced in CMP of Icsbp À/À mice (Figure 3a).…”

“…Oncogene (2008) 27, 3865-3869;doi:10.1038/sj.onc.1211043;published online 28 January 2008 Keywords: Meis1; Meis3; Icsbp; AML Interferon consensus sequence-binding protein (ICSBP) (also known as interferon regulatory factor-8) is a transcriptional repressor that acts as a tumor suppressor in myeloid neoplasia. Icsbp-deficient mice exhibit early symptoms of chronic myeloid leukemia (CML) (Holtschke et al, 1996) due to altered sensitivity of early myeloid progenitors to proliferative or apoptotic stimuli (Gabriele et al, 1999;Scheller et al, 1999;Burchert et al, 2004;Schmidt et al, 2004;Zhu et al, 2004). Downregulation of Icsbp is required for the induction of a CML-like syndrome by BCR-ABL in murine bone marrow (BM) gene transfer experiments (Hao and Ren, 2000) and Icsbp deficiency collaborates with AML-ETO or NUP98-TOP1 leukemia fusion gene products in the progression to acute myeloid leukemia (AML) (Schwieger et al, 2002;Gurevich et al, 2006).…”