Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

Abstract

Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. Leukemia (2012Leukemia ( ) 26, 2027Leukemia ( -2031 doi:10.1038/leu.2012 Keywords: CLL; MDS; mutations; spliceosome INTRODUCTIONIn a series of recently published work, the coding sequences of the DNA obtained from mononuclear cells of the bone marrow of patients with myelodysplastic syndromes (MDSs) were compared with presumably germline DNA (T lymphocytes or buccal swab). [1][2][3] The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations. 1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA. Such mutations were mutually exclusive and were detected in 45-85% of patients with MDS; 1 the majority constituted missense mutations located in restricted regions of proteins.A similar analysis was conducted in chronic lymphocytic leukemia (CLL) where DNA from tumor cells (CD19 þ and CD5 þ lymphocytes) was compared with that of non-tumor cells (granulocytes or fibroblasts). [4][5][6][7] In addition to genes already known to be mutated in this disease, such as TP53 and ATM, 11 genes were found to be recurrently affected. 4,6 The pathway analyses predicted that these mutations affected DNA damage repair and cell cycle, the Wnt, NOTCH1 and inflammatory/TLR signaling pathways, and, as was the case in MDS, control of splicing mechanisms. 4 The common novel observation, from the above-mentioned studies, in both MDS and CLL, was the identification of mutations in genes whose products are involved in the control of RNA splicing. 8 The involvement of oncogenes in RNA processing h...

A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor pharmacophore

“…4, 5 Recent groundbreaking discoveries have identified recurrent mutations in SF3B1 (and/or other splicing factors) in multiple forms of cancer including: myelodysplastic syndromes (MDS), 14,28 chronic lymphocytic leukemia (CLL), 29 acute myeloid leukemia (AML), 30,31 breast cancer, 32, 33 lung adenosarcoma, 34 and uveal melanoma. 35 These genetic studies have also fueled complementary research in the therapeutic significance of spliceosome recurrent mutations.…”

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

“…Although treatment has undergone profound improvements in recent years [4][5][6] , CLL shows a remarkable clinical variability which is likely to be reflective of a large biological heterogeneity 7,8 .…”

SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing

“…Interestingly, recent genomewide sequencing studies revealed that mutations in genes encoding splicing factors are commonly associated with MDS and other hematological malignancies (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). One of these newly identified genes codes for the SRSF2 splicing factor (also known as SC35), and its mutations have been linked to poor survival among MDS patients (16,17).…”