Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing

Abstract

Acute myeloid leukemia (AML) is characterized by molecular heterogeneity. As commonly altered genomic regions point to candidate genes involved in leukemogenesis, we used microarray-based comparative genomic hybridization and single nucleotide polymorphism profiling data of 391 AML cases to further narrow down genomic regions of interest. Targeted resequencing of 1000 genes located in the critical regions was performed in a representative cohort of 50 AML samples comprising all major cytogenetic subgroups.We identified 120 missense/nonsense mutations as well as 60 insertions/deletions affecting 73 different genes (ϳ 3.6 tumorspecific aberrations/AML). While most of the newly identified alterations were nonrecurrent, we observed an enrichment of mutations affecting genes involved in epigenetic regulation including known candidates like TET2, TET1, DNMT3A, and DNMT1, as well as mutations in the histone methyltransferases NSD1, EZH2, and MLL3. Furthermore, we found mutations in the splicing factor SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21. These splicingrelated mutations affected 10% of AML patients in a mutually exclusive manner. In conclusion, we could identify a large number of alterations in genes involved in aberrant splicing and epigenetic regulation in genomic regions commonly altered in AML, highlighting their important role in the molecular pathogenesis of AML. (Blood. 2012;120(18):e83-e92)

Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34 + progenitors

“…The p.P214L, p.R396G and p.A377T variants were present in digestive tract tumors, 26 while p.Y401C has been associated with AML. 27 More recently, germline ETV6 variants have also been found to predispose to cancer. Eleven patients carrying mutETV6 (p.P214L, p.R399C, p.R369Q, p.L349P, p.N385fs or p.W380R) developed acute lymphocytic leukemia or myelodysplastic syndrome.…”

Aberrant RNA splicing and mutations in spliceosome complex in acute myeloid leukemia

“…However, SFPQ is not an essential member of spliceosome, but rather act as a molecular scaffold and involve cotranslational and alternative splicing (93). Mutations in SFPQ and in the nonclassic regulators of mRNA processing CTCF and RAD21 have been discovered in 10% of AML patients in a mutually exclusive manner (94). However, the clinical importance of this mutation has not been confirmed.…”

Gene mutations of acute myeloid leukemia in the genome era

“…Cohesion complex is composed by Smc1, Smc3, Rad21 and SA1/2. SA2-encoding gene, STAG2, and RAD21 are reported to be deleted in AML genome, and recently SMC1A, SMC3, STAG2 and RAD21 are found to be mutated in a loss-offunction manner [40,80,81]. The mutations are found in a variety of AML except acute promyelocytic leukemia and are unrelated to chromosomal instability.…”