Alterations in IRF1/IRF2 expression in acute myelogenous leukemia

Abstract

The interferon response genes 1 and 2 have been shown to be involved in the regulation of differentiation and proliferation of cells of the myeloid series, with the former functioning as an anti-oncogene and the latter as an oncogene. In the study described here, the levels of expression of these two genes and the ratio of their expression were compared in AML and normal marrow. The ratio of gene expression was significantly less in AML marrow cells as compared to normal marrow cells [med ratio = 1.33 vs. 2.97, P = 0.003]. While the expression ratio was unaffected by the presence or absence of either ras or fms mutations, p53 mutations were associated with higher IRF1:IRF2 expression ratios that wt p53 genes [med = 1.701 vs. 1.135, P = 0.014]. Given the functional characteristics and the competitive nature of these two genes, it is possible that leukemic transformation is associated with a fall in IRF1:IRF2 ratios. Finally, the administration of IL4 can result in the normalization of the IRF1:IRF2 ratio in the marrow cells of some patients with AML.

Universal attenuators and their interactions with feedback loops in gene regulatory networks

“…Remarkably, a single four-gene LRC, composed by EGR1, IRF1, POLR3A and IRF1, can be found in the tail of the longest LRCs ( Figure 6A), emanating from the feedback loops. Our theoretical analysis suggests that the dynamics of the final gene of this chain (IRF1) is highly constrained by the LRC, and biological experimentation indicates that IRF1 is a tumour suppressor gene relevant to a number of cancers including leukaemia (39)(40)(41). Our theoretical interpretation is that the dynamics of LRCs is exploited by cancer cells to inhibit the proper activity of this gene.…”

“…These genes are therefore likely to be encountered in relatively long LRCs, and hence conceivably have very limited RE. Notably, all of these genes have been shown to have an important role in the survival of leukaemia cells (NFE2 (42), POLR3A (43), JunD (44), Myc (45), GATA2 (46), NR4A1 (47), IRF3 (48), IRF1 (39)(40)(41)) suggesting that cancer cells may be dynamically controlling the variation of these genes.…”

“…The longest LRCs are composed of 14 TFs and one non-TF gene ( Figure 5B and C, and Figure 6A). Interestingly, the 'tail' of the longest LRCs contains several genes that are often dysregulated in cancer: EGR1 (33)(34)(35), IRF3 (36), POLR3A (37) and IRF1 (38,39).…”

HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors

“…51 Many recent reports aimed to define the characteristics of leukemic progenitor cells present in AML have shown the constitutive activation of transcription factors like STATs 52 or NF-kB, 9 as well as aberrant expression of tumor suppressor genes IRF1 and DAPK. 8,53 Data reported in this paper indicate the herg gene as the first K + channel enco-ding gene which is constitutively up-regulated in AML blasts, being completely turned off either in mature myeloid cells and in resting CD34 + cells.…”

A retroviral library genetic screen identifies IRF-2 as an inhibitor of N-ras-induced growth suppression in leukemic cells

“…Moreover, functional inactivation of IRF-1, as a result of high constitutive IRF-2 expression (with no detectable inactivation of IRF-1) has also been observed in approximately 70% of cases of AML (Preisler et al, 2001). Since IRF-1 appears to mediate a tumorsuppressive response to dysregulated ras signaling, it seems likely that ras mutations and IRF-1 inactivation cooperate during myeloid leukemogenesis.…”