| Entity | Multiple Myeloma (MM) |
| Disease | The proto-oncogene IRF4 is deregulated in MM with translocation t(6;14)(p25;q32). IRF4 is also deregulated in B-cell non Hodgkin lymphoma (NHL) and in particular in diffuse large B-cell lymphoma (DLBCL).
MM is a malignant monoclonal plasma cell proliferation that has a complex molecular aetiology with several subgroups defined by gene expression profiling and recurrent chromosomal translocations.
IRF4 inhibition is toxic to myeloma cell lines, regardless of the precise transforming oncogenic mechanism. MYC is a direct target of IRF4 gene in activated B-cells and in mMM. IRF4 is itself a direct target of MYC transactivation, generating an autoregulatory circuit in myeloma cells. |
| Cytogenetics | t(6;14)(p25;q32) --> IRF4 - IgH.
Possibly other translocations of IRF4 with unidentified partner chromosomes have been identified. Translocations involving 14q32 are found in a significant fraction of patients, and include t(6;14)(p25;q32). |
| Hybrid/Mutated Gene | The translocation juxtaposes the IgH locus to the IRF4 gene. |
| Oncogenesis | The chromosomal translocation t(6;14)(p25;q32) in MM may cause transcriptional activation of the IRF4 proto-oncogene. As a result of the translocation, IRF4 is overexpressed, and this event may contribute to tumorigenesis in vitro. |
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| Entity | B-cell chronic lymphocytic leukemia (B-CLL) |
| Disease | B-CLL is the most common form of leukemia in the Western world. The disease presents a heterogeneous clinical course, with some patients surviving for many years without requiring any specific therapy and others progressing rapidly despite aggressive treatment. |
| Prognosis | It is not yet clear if the presence of IRF4 expression in B-CLL represents a favourable or unfavourable prognostic marker. In fact, previous studies have demonstrated a variable expression of IRF4 in B-CLL patients and a conflicting prognostic significance. |
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| Entity | Adult T-cell leukemia (ATL) |
| Disease | ATL is an aggressive leukemia of CD4+ T lymphocytes and is also associated with a neurological demyelinating disease, tropical spastic paraparesis (TSP) or HTLV-1 Associated Myelopathies (HAM). The human T cell leukemia/lymphotrophic virus-1 (HTLV-1) is the aetiologic agent of ATL, and the disease is geographically localized to regions of the world where HTLV infection is endemic. IRF4 was shown to be highly expressed in cells derived from patients with ATL and in HTLV-1 infected cell lines. IRF4 expression increases during the progression of ATL, with IRF4 expression levels highest during the late acute phase of ATL. |
| Oncogenesis | IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle. IRF4 transcriptional downregulation would lead to an overall decrease in DNA repair and a subsequent increase in cellular mutations, thus contributing to cellular transformation. |
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| Entity | Primary effusion lymphoma (PEL) |
| Disease | PEL is a clinico-pathological category of B-cell non-Hodgkin's lymphoma (NHL) based on the infection of the tumour clone by human herpesvirus type-8/Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV). PEL preferentially develops in immunodeficient patients and displays a marked preference for liquid growth in the serous body cavities in the absence of clinically identifiable tumour masses. Although PEL belongs to the B-cell lineage, the overwhelming majority of cases exhibit a non-B, non-T phenotype, lacking expression of surface immunoglobulins (Ig) and common B cell associated. |
| Oncogenesis | IRF4 expression in PEL is a result of the stage of differentiation of the tumour clone. At present, the role of IRF4 expression in PEL growth is yet unknown, although it has been documented that IRF4 is capable of inducing transformation in experimental cellular systems. |
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