Enforced expression of MIR142, a target of chromosome translocation in human B-cell tumors, results in B-cell depletion

Abstract

MicroRNA142 (MIR142) is a target of chromosome translocations and mutations in human B-cell lymphomas. We analyzed an aggressive B-cell lymphoma carrying t(8;17)(q24;q22) and t(6;14)(p21;q32), and sought to explore the role(s) of MIR142 in lymphomagenesis. t(8;17)(q24;q22) involved MYC on 8q24 and pri-MIR142 on 17q22. MYC was activated by a promoter substitution by t(8;17)(q24;q22). t(8;17)(q24;q22) was an additional event after t(6;14) (p21;q32), which caused the over-expression of CCND3. Southern blot analyses revealed that the MIR142 locus was deleted from the affected allele, whereas Northern analyses showed over-expression of MIR142 in tumor cells. Although previous studies reported an over-expression of mutations in MIR142 in B-cell lymphomas, limited information is available on the functions of MIR142 in lymphomagenesis. Therefore, we generated bone marrow transplantation (BMT) and transgenic (Eμ/mir142) mice, which showed enforced expression in hematopoietic progenitor cells and B cells, respectively. BMT mice showed decreased numbers of all lineage-positive cells, particularly B cells, in peripheral blood. Eμ/mir142 mice showed decreased numbers of IgM-positive splenocytes, and exhibited altered B-cell phenotypic changes induced by lipopolysaccharide. Our results suggest that over-expression of MIR142 alters B-cell differentiation, implying multi-step lymphomagenesis together with MYC activation and CCND3 over-expression.

Exploring the Relationship between Fusion Genes and MicroRNAs in Cancer

“…This specific region, 8q24.21, codes for MYC proto-oncogene, and the region, 17q22, codes for miR-142, translocation of the c-Myc locus, have been reported in leukemia patients affected by aggressive B-cell malignancy [12][13][14]. Further, the tumor cells with t(8;17)(q24;q22) translocation were shown to have a higher miR-142 expression [13]. It is evident that the t(8;17) fusion is presumably accountable for MYC activation because of promoter substitution [12,13].…”

miR-142: A Master Regulator in Hematological Malignancies and Therapeutic Opportunities

“…Kuriyama et al reported an interesting case of a patient with aggressive DLBCL who exhibited chromosomal translocations involving the miR-142 locus and had previously developed autoimmune hemolytic anemia [ 117 ]. The t(8;17)(q24;q22) chromosomal translocation resulted in the deletion of miR-142 in the affected allele and the upregulation of MYC by flanking it with a miR-142 promoter [ 117 ]. Perhaps due to a compensatory reaction after allelic deletion, in vivo studies found miR-142 to be overexpressed, leading to B-cell depletion and altered phenotypes in differentiation [ 117 , 129 ].…”

“…The t(8;17)(q24;q22) chromosomal translocation resulted in the deletion of miR-142 in the affected allele and the upregulation of MYC by flanking it with a miR-142 promoter [ 117 ]. Perhaps due to a compensatory reaction after allelic deletion, in vivo studies found miR-142 to be overexpressed, leading to B-cell depletion and altered phenotypes in differentiation [ 117 , 129 ]. Additional investigations are necessary to fully understand the mechanisms involved with these effects, but these findings suggest that deletions in miR-142 can also play a role in DLBCL.…”

Non-coding RNAs in cancers with chromosomal rearrangements: the signatures, causes, functions and implications

“…This DNA increase could also be found at the regulatory region of ncRNAs. miR-142 is overexpressed in a subtype of B-cell tumors with t(8;17)(q24;q22) translocation (Kuriyama et al, 2018). Although the translocation involved pri-miR-142, it does not result in upregulation as the pri-miR-142 locus was truncated in the affected allele.…”

“…Although the translocation involved pri-miR-142, it does not result in upregulation as the pri-miR-142 locus was truncated in the affected allele. Instead, a germline band with increased intensity suggests a gain in the upstream region of pri-miR-142 (Kuriyama et al, 2018). In addition, gain of DNA copies was reported on lncRNAs, such as PVT1 in PML–RARA-driven APL (Zeng et al, 2015).…”