MCL1

Overview

First described 1993. Earliest sequence paper UniProt cites for the protein: Kozopas K.M. et al, Proc. Natl. Acad. Sci. U.S.A, 1993, "MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2". Source.

Sources: HGNC HGNC:6943 (approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)); UniProt Q07820 (protein name, function text, keywords and locations (REST API)); CIViC gene MCL1 (1 evidence items, 0 assertions, 1 variants; diseases: Multiple Myeloma (GraphQL API, CC0))

• Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: CIViC lists 1 therapies; CIViC holds 1 clinical evidence items on its variants. Evidence tier "approved-drug" is the strongest of those signals.
• Prevalence not recorded: none of the sources gives a positivity rate.
• Lymphoma, BCL2 and t(14;18): The t(14;18) translocation puts BCL2 under the control of the immunoglobulin heavy-chain enhancer, so the cell makes an anti-apoptotic protein at a level a germinal-centre B cell is never meant to have. The sequencing of the breakpoints showed that the translocation is a mistake made by the VDJ recombinase at the pre-B-cell stage: the chromosome 18 segment recombines with the JH segment on chromosome 14, with extraneous N-region nucleotides at the junction and signal-like sequences near the chromosome 18 breakpoint (Tsujimoto 1985). The lesion is therefore not a late event in a lymphoma but the first event, made in the bone marrow years before. Frequency: BCL2 rearrangement in 13.5% of 442 unselected diffuse large B-cell lymphomas in the RICOVER trial (Horn 2013), and in the large majority of follicular lymphomas. A t(14;18)-bearing B cell can be found in the blood of healthy people, so the translocation alone is not a disease. What it changes about treatment: Less than it should. Venetoclax, which displaces the pro-apoptotic partners from BCL-2 directly, transformed chronic lymphocytic leukaemia and has not transformed follicular or diffuse large B-cell lymphoma, where the cells also depend on MCL1 and BCL-xL. A BCL2 rearrangement is used for diagnosis and, in combination with MYC, for risk, not for drug choice.