Rare t(X;14)(q28;q32) translocation reveals link between MTCP1 and chronic lymphocytic leukemia

Abstract

Rare, recurrent balanced translocations occur in a variety of cancers but are often not functionally interrogated. Balanced translocations with the immunoglobulin heavy chain locus (IGH; 14q32) in chronic lymphocytic leukemia (CLL) are infrequent but have led to the discovery of pathogenic genes including CCND1, BCL2, and BCL3. Following identification of a t(X;14)(q28;q32) translocation that placed the mature T cell proliferation 1 gene (MTCP1) adjacent to the immunoglobulin locus in a CLL patient, we hypothesized that this gene may have previously unrecognized importance. Indeed, here we report overexpression of human MTCP1 restricted to the B cell compartment in mice produces a clonal CD5+/CD19+ leukemia recapitulating the major characteristics of human CLL and demonstrates favorable response to therapeutic intervention with ibrutinib. We reinforce the importance of genetic interrogation of rare, recurrent balanced translocations to identify cancer driving genes via the story of MTCP1 as a contributor to CLL pathogenesis.

A prognostic 15-gene model based on differentially expressed genes among metabolic subtypes in diffuse large B-cell lymphoma

“…The favorable effect of FGD6 on prognosis in DLBCL needs further investigation. In addition, the over-expression of CMC4 (also known as MTCP1 ), as a favorable prognosis gene in our model, was discordantly reported to produce clonal CD5 + /CD19 + leukemia in mice ( 45 ), which was thought to be a chronic lymphocytic leukemia driving gene. For the remaining genes, OR10A3 , RPF1 , KΑTNA1 , and CES4A , in our risk score model, no specific relationship to cancer had been reported yet, further exploration should be carried out for their roles in the prognosis in DLBCL patients.…”

Identification and validation of three potential biomarkers and immune microenvironment for in severe asthma in microarray and single-cell datasets

“…Nuclear factor (NF)-κB is a key factor in the normal development and homeostasis of the immune system, controlling the transcription of in ammatory cytokines and chemokines, it is also a protein involved in antigen presentation, and a regulator of cell death and proliferation (33).B-cell lymphoma factor 3 (BCL3) is an atypical member of the ikappa B inhibitor (IkB) family, which activates or inhibits gene transcription by combining with two members of the nuclear factor NF-kB family, p50 or p52 homodimers (34,35). BCL3 is implicated with the development and progression of many diseases and malignancies (36), such as hematological tumors (37). In addition to this, in in ammatory effects, BCL3 is widely considered as an anti-in ammatory factor that is essential in promoting B cell development, differentiation, survival and proliferation of Th cells, and terminal differentiation of dendritic cell functions (38-40).…”

VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia

“…All animal studies were carried out under protocols approved by The Ohio State University Institutional Animal Care and Use Committee (IACUC). Previously, 1 × 10 6 splenocytes from Eµ-MTCP1 mice, which recently were described to mimic human CLL, were resuspended in PBS and injected via tail vein into male C57BL/6 J from The Jackson Laboratory [32]. Mice were monitored for development of peripheral disease by flow cytometry, measuring the percentage of CD5 + /CD19 + cells in peripheral blood.…”

“…Next, we sought to assess the in vivo efficacy of VIP152 to better evaluate its potential clinical utility in patients with CLL. To accomplish this we used a novel transgenic model of CLL (Eµ-MTCP1 model) developed recently by our group that is characterized by CD5 + /CD19 + and B220 Dim expansion in the blood [32]. Splenocytes from diseased Eµ-MTCP1 mice were serially engrafted via tail vein injection and monitored for leukemia via weekly flow cytometry (Fig.…”