Identification of functional cooperative mutations of SETD2 in human acute leukemia

Abstract

Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy1,2, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene3 and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase)4. Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

“…We compared the false positive and negative rates, sensitivity, and accuracy of CASpoint in SNV calling with the performances of other published software installed in the Beijing Institute of Genomics (BIG) computational center and bioinformatics facility, including Mutect (43), SomaticSniper (44), JoinSNVmix (45), Varscan2 (46), and Samtools (47). Simulated sequencing reads in the SMC and a large set of whole-genome or -exome sequencing reads produced from various genomics projects in solid tumors (31) and leukemia (48) in Beijing Institute of Genomics were used to evaluate the performance of CASpoint. The overall accuracy of CASpoint is comparable to the others for the SMC simulated reads.…”

“…As described in Zhu et al (48), two statistical tests are introduced in the program. One-sided Fisher testing calculates the statistical significance of tumor mutant allele frequency (MAF) that is higher in the tumor population than in the normal cell population.…”

Epigenetic Modifications: Therapeutic Potential in Cancer

“…Histone lysine methyltransferases (SETD1 and 2) are found as novel tumor suppressors. Downregulation of SETD2 promotes both initiation and progression in leukemia (Zhu et al 2014), whereas hSETD1A controls tumor metastasis by activating MMP expression (Salz et al 2014). An upregulation of EZH2 (Enhancer of Zeste 2, a histone methyltransferase) has been observed in a wide variety of tumors, such as prostate cancer, lymphomas, colorectal and gastric cancer, and bladder and breast cancer.…”

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

“…Transcription elongation NSD1, NSD2 [263] , SET2 [264] , SMYD2 [232] , MMSET [265] ASH1 [266] , JHDM1 [267] , JHDM1A/KDM2A, JHDM1B/KDM2B [268] ISW1B [269] H4K20 me1 me2 me3 (non-genic regions, centromeric heterochromatin, satellite sequences, long terminal repeats Transcritional silencing, heterochromatin, repression of proinflammatory genes PR-SET7/SET8 [270] SUV420H1, SUV420H2 [274] SUV420H2 [274] , SMYD5 [275] PHF8 [271] PHF2 [275] PHF2 [275] L3MBTL1 [272] PHF20 [276] , L3MBTL1 [277] NcoR [275] [ gene [158] . Furthermore, it is well known that a considerable amount of integrated vectors become silent [159] , and this effect seems to be dependent on the promoter chosen to drive the ectopic expression of the gene [160,161] .…”