Mutant U2AF1-induced alternative splicing of H2afy (macroH2A1) regulates B-lymphopoiesis in mice

Abstract

Mutant U2AF1-induced alternative splicing of H2afy (macroH2A1) regulates B-lymphopoiesis in mice Graphical abstract Highlights d Mutant U2AF1(S34F) induces alternative splicing of H2AFY d H2afy À/À mice have defective B cell development similar to U2AF1(S34F) mice d The H2afy1.1 splice isoform, reduced by U2AF1(S34F), regulates B cell development d H2AFY occupies the Ebf1 promoter, a master regulator of B cell development

Recurrent Spliceosome Mutations in Cancer: Mechanisms and Consequences of Aberrant Splice Site Selection

“…Transgenic mice expressing the U2AF1 S37F mutation display various abnormalities associated with MDS, including peripheral blood leukopenia, reduction in B cells and monocytes in the bone marrow, and bone marrow progenitor cell expansion [ 16 , 20 ]. In addition, transcriptome analysis of common myeloid progenitors (CMPs) from transgenic mice identified U2AF1 S34F -dependent gene expression alteration in genes belonging to immune response and leukocytic activation processes [ 16 ].…”

“…Nevertheless, U2AF1 S34F transgenic mice do not develop MDS or AML [ 16 ]. Although U2AF1 MUT does not generate widespread splicing alterations, altered splicing events driven by U2AF1 MUT belong to mutated genes in MDS and AML (ASXL1, GNAS, PICALM) and involved in cancer hallmarks, including stem cell biology (MED24), transcription regulation (H2AFY), replication stress response pathway (ATR), and innate immune pathway (IRAK4) [ 16 , 20 , 54 , 59 ].…”

“…The defects in B cell development observed in U2AF1 S34F transgenic mice [ 20 ] have been associated with U2AF1 S34F -mediated splicing alterations of the transcript of histone variant H2AFY (macroH2A1), which is associated with both transcription repression and transcription activation [ 60 ]. Two different isoforms are generated by the mutually exclusive inclusion of exon 6a and exon 6b, leading to H2AFY1.2 and H2AFY1.1, respectively ( Figure 4 C).…”

“…Interestingly, H2AFY knock-out (KO) mice present the same B cell development defects, but not the additional MDS features observed in U2AF1 S34F transgenic mice [ 20 ]. Moreover, the expression of H2AFY1.1, but not H2AFY1.2, rescues the B cell development defects observed in both H2AFY KO and U2AF1 S34F transgenic mice [ 20 ]. These results mechanistically link the U2AFY splicing alteration to the defects in B cell development observed in U2AF S34F transgenic mice.…”

“…Three specific components of complex A have recently gained attention as they are recurrently mutated in various cancer types and affect the very first step in the splicing cycle: the U1 snRNA, which is essential for 5′ splice site recognition, the U2 snRNP component SF3B1 and the U2 auxiliar factor subunit U2AF1, both of which are involved in 3′ splice site selection [ 15 , 16 , 17 , 18 , 19 , 20 ]. Elegant studies that took advantage of whole-transcriptome analysis and in vivo and in vitro models have revealed the consequences of such spliceosome mutations and their impact on cancer development and progression [ 15 , 16 , 17 , 18 , 19 , 20 ]. Here, we review the current knowledge about the genetic characteristics of U1 snRNA, SF3B1, and U2AF1 somatic mutations and the mechanism by which they influence splicing decision and, as a consequence, tumor development.…”