Abnormal epigenetic regulation has been implicated in oncogenesis. We report here the identification of somatic mutations by exome sequencing in acute monocytic leukemia, the M5 subtype of acute myeloid leukemia (AML-M5). We discovered mutations in DNMT3A (encoding DNA methyltransferase 3A) in 23 of 112 (20.5%) cases. The DNMT3A mutants showed reduced enzymatic activity or aberrant affinity to histone H3 in vitro. Notably, there were alterations of DNA methylation patterns and/or gene expression profiles (such as HOXB genes) in samples with DNMT3A mutations as compared with those without such changes. Leukemias with DNMT3A mutations constituted a group of poor prognosis with elderly disease onset and of promonocytic as well as monocytic predominance among AML-M5 individuals. Screening other leukemia subtypes showed Arg882 alterations in 13.6% of acute myelomonocytic leukemia (AML-M4) cases. Our work suggests a contribution of aberrant DNA methyltransferase activity to the pathogenesis of acute monocytic leukemia and provides a useful new biomarker for relevant cases.

Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.

Arsenic had been used in treating malignancies from the 18th to mid-20th century. In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia-retinoic acid receptor ␣ (PML-RAR␣) fusion. Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signaling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RAR␣, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation/ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PML-RAR␣ for degradation through its RAR␣ moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits. The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine. (Blood. 2011;117(24):6425-6437) IntroductionArsenic is the 20th most abundant element in the earth's crust. 1 It is a chemical analog of phosphorus and lies directly below P in the periodic table. A unique feature of arsenic is its extremely paradoxical abilities: it is toxic to humans, animals, and plants, but is used instead of phosphorus by a recently isolated bacterium 2 ; it kills people, but saves lives; it can cause some cancers but cures others such as the acute promyelocytic leukemia (APL) 3 ; it is one of the oldest drugs in the world but was progressively revived between the 1970s and 1990s, because of its striking efficacy on APL, which represented the most malignant type of acute leukemia. 3 These paradoxical effects of arsenic reflect its unique metabolism and multiple properties. 4 In this review, we address how arsenic rebuilds its reputation from a notorious poison to a new lease of life by mechanistic molecular and translational medicine studies. Arsenic in natureArsenic is the 33rd element in the periodic table and exists ubiquitously in either inorganic or organic forms, pure metallic arsenic being rarely found in nature. Arsenic occurs in 5 different valence states, ϩV (arsenate), ϩIII (arsenite), ϩI (arsonium metal), 0 (arsenic), and ϪIII (arsine). 5 Most arsenic compounds have no smell or special taste and are white or colorless powders that do not evaporate. Arsenic gets into air when contaminated materials are burned. Inorganic arsenic occurs naturally in soils and sedimentary rocks such as mineral...