With similar results, fusions between MUM1 and IgH loci were observed by means of interphase DCFISH in eight (21.1%) out of the 38 MM cases, although no definite relationships between MUM1 status and specific clinical findings could be established.
The cellular interferon regulatory factor-4 (IRF-4), which is a member of IRF family, is involved in the development of multiple myeloma and Epstein-Barr virus (EBV)-mediated transformation of B lymphocytes.
MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma.
For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10<sup>-5</sup> with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site.
These data confirm the central role of IRF4 in MM pathogenesis; indicate that this is an important mechanism by which lenalidomide exerts its antitumour effects; and may provide a mechanistic biomarker to predict response to lenalidomide.
Recently, high expression levels of cereblon (CRBN) and MUM1 have been associated with better response rates in multiple myeloma treated with lenalidomide.
Here we show, using a loss-of-function, RNA-interference-based genetic screen, that IRF4 inhibition is toxic to myeloma cell lines, regardless of transforming oncogenic mechanism.
The Interferon Regulatory Factor 4 (IRF4) gene encodes a transcription factor important for key developmental stages of hematopoiesis, with known oncogenic implications in multiple myeloma, adult leukemias and lymphomas.
One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment.
In addition, malignant cells strongly stained with CD138 in all the cases, whereas leukocyte common antigen and multiple myeloma 1/interferon regulatory factor 4 were completely negative, nor immunoreactivity was seen for either κ or λ light chains.
Knockdown of Gls1 increased the expression of Cdkn1a and Cdkn1b and decreased the expression of some critical oncogenes for cancer cell survival, such as c-Myc, Cdk4, and NfκB, as well as some genes which are essential for MM cell survival, such as Irf4, Prdm1, Csnk1α1, and Rassf5.
Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells.Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells.
These results for the first time indicate that a crosstalk between IRF4 and Th17 cells is associated with MM prognosis, and IRF4 may be served an important target for MM immunotherapy.
Although IRF4 is not genetically altered in most myelomas, they are nonetheless addicted to an aberrant IRF4 regulatory network that fuses the gene expression programmes of normal plasma cells and activated B cells.
The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro.
Our results indicate that the KDM3A-KLF2-IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.
Diffuse large B-cell lymphoma (DLBCL) can be assigned to prognostic subgroups, including germinal center B-cell (GCB) and activated B-cell subgroups, by using gene expression profiling and, reportedly, immunohistochemistry for CD10, Bcl-6, and multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4).