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Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

In this study, three geophysical techniques were used to identify, localize, and characterize a partly blind fault in the Llano Grande basin within the Agua Fría Graben. This tectonic basin is located in the Los Azufres Volcanic Complex, one of the major silicic volcanic centers in the Trans-Mexican Volcanic Belt. The 1 km wide Agua Fría graben could be considered as an analogous of the larger graben structures bounded by the Morelia-Acambay Fault System. Since it is filled by recent sediments, it represents a challenge for the recognition and characterization of active faults that lack clear surface expression. Newly collected magnetic data led to the identification of lineaments interpreted as structural discontinuities. Ground penetrating radar and seismic refraction surveys were carried out across one of these magnetic lineaments crossing the basin to characterize the nature and geometry of the inferred discontinuity. The ground penetrating radar profiles allowed the identification of buried deformational structures interpreted as the northern segment of the Agua Fría fault. The subsurface reflectors displaced 1 to 1.5 m by the fault indicate that this structure is potentially active. The opening of trenches based on these results makes it possible to confirm the interpretation of the geophysical profiles, to discuss the precision of the data and to validate their use for such studies. On seismic refraction profiles, the deformation zones are related to low P-wave velocity zones. These geophysical studies demonstrate the potential of such techniques to locate faults in the subsurface, partially characterize the width of the fault zone and the associated displacement within the uppermost of the subsurface. Our results may be applied to define ideal sites for paleoseismic excavations which are essential for the identification and description of historical and prehistoric earthquakes, and thus, for the characterization of the local seismic hazard.

Mutations in SETD2, encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia. We investigated the impact of SETD2 mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2. SETD2 mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non-DNA damaging agent, l-asparaginase. H3K36me3 localizes components of the DNA damage response (DDR) pathway and SETD2 mutation impaired DDR, blunting apoptosis induced by cytotoxic chemotherapy. Consistent with local recruitment of DDR, genomic regions with higher H3K36me3 had a lower mutation rate, which was increased with SETD2 mutation. Heterozygous conditional inactivation of Setd2 in a murine model decreased the latency of MLL-AF9-induced leukemia and caused resistance to cytarabine treatment in vivo, whereas homozygous loss delayed leukemia formation. Treatment with JIB-04, an inhibitor of the H3K9/36me3 demethylase KDM4A, restored H3K36me3 levels and sensitivity to cytarabine. These findings establish SETD2 alteration as a mechanism of resistance to DNA-damaging chemotherapy, consistent with a local loss of DDR, and identify a potential therapeutic strategy to target SETD2-mutant leukemias.