Alan H. Shih
Memorial Sloan Kettering Cancer Center
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Publication
Featured researches published by Alan H. Shih.
Nature Reviews Cancer | 2012
Alan H. Shih; Omar Abdel-Wahab; Jay Patel; Ross L. Levine
Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.
The EMBO Journal | 2013
Rachel Deplus; Benjamin Delatte; Marie K. Schwinn; Matthieu Defrance; Jacqui Mendez; Nancy Murphy; Mark A. Dawson; Michael Volkmar; Pascale Putmans; Emilie Calonne; Alan H. Shih; Ross L. Levine; Olivier A. Bernard; Thomas Mercher; Eric Solary; Marjeta Urh; Danette L. Daniels; François Fuks
TET proteins convert 5‐methylcytosine to 5‐hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O‐GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3–OGT co‐localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3–OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step‐wise model, involving TET–OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation.
Journal of Experimental Medicine | 2013
Omar Abdel-Wahab; Jie Gao; Mazhar Adli; Anwesha Dey; Thomas Trimarchi; Young Rock Chung; Cem Kuscu; Todd Hricik; Delphine Ndiaye-Lobry; Lindsay M. LaFave; Richard Koche; Alan H. Shih; Olga A. Guryanova; Eunhee Kim; Sheng Li; Suveg Pandey; Joseph Yusup Shin; Leon Telis; Jinfeng Liu; Parva K. Bhatt; Sebastien Monette; Xinyang Zhao; Christopher E. Mason; Christopher Y. Park; Bradley E. Bernstein; Iannis Aifantis; Ross L. Levine
Loss of Asxl1 results in myelodysplastic syndrome, whereas concomitant deletion of Tet2 restores HSC self-renewal and triggers a more severe disease phenotype distinct from that seen in single-gene knockout mice.
Cancer Cell | 2015
Alan H. Shih; Yanwen Jiang; Cem Meydan; Kaitlyn Shank; Suveg Pandey; Laura Barreyro; Iléana Antony-Debré; Agnes Viale; Nicholas D. Socci; Yongming Sun; Alexander Robertson; Magali Cavatore; Elisa de Stanchina; Todd Hricik; Franck Rapaport; Brittany A. Woods; Chen Wei; Megan Hatlen; Muhamed Baljevic; Stephen D. Nimer; Martin S. Tallman; Elisabeth Paietta; Luisa Cimmino; Iannis Aifantis; Ulrich Steidl; Christopher E. Mason; Ari Melnick; Ross L. Levine
Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2(-/-);Flt3(ITD) progenitors (LSK CD48(+)CD150(-)) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3(ITD) mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.
Cell Reports | 2014
Jozef Madzo; Hui Liu; Alexis Rodriguez; Aparna Vasanthakumar; Sriram Sundaravel; Donne Bennett D. Caces; Timothy J. Looney; Li Zhang; Janet B. Lepore; Trisha Macrae; Robert Duszynski; Alan H. Shih; Chun-Xiao Song; Miao Yu; Yiting Yu; Robert L. Grossman; Brigitte Raumann; Amit Verma; Chuan He; Ross L. Levine; Don Lavelle; Bruce T. Lahn; Amittha Wickrema; Lucy A. Godley
Hematopoietic stem cell differentiation involves the silencing of self-renewal genes and induction of a specific transcriptional program. Identification of multiple covalent cytosine modifications raises the question of how these derivatized bases influence stem cell commitment. Using a replicative primary human hematopoietic stem/progenitor cell differentiation system, we demonstrate dynamic changes of 5-hydroxymethylcytosine (5-hmC) during stem cell commitment and differentiation to the erythroid lineage. Genomic loci that maintain or gain 5-hmC density throughout erythroid differentiation contain binding sites for erythroid transcription factors and several factors not previously recognized as erythroid-specific factors. The functional importance of 5-hmC was demonstrated by impaired erythroid differentiation, with augmentation of myeloid potential, and disrupted 5-hmC patterning in leukemia patient-derived CD34+ stem/early progenitor cells with TET methylcytosine dioxygenase 2 (TET2) mutations. Thus, chemical conjugation and affinity purification of 5-hmC-enriched sequences followed by sequencing serve as resources for deciphering functional implications for gene expression during stem cell commitment and differentiation along a particular lineage.
Haematologica | 2013
Alan H. Shih; Stephen S. Chung; Emily K. Dolezal; Su Jiang Zhang; Omar Abdel-Wahab; Christopher Y. Park; Stephen D. Nimer; Ross L. Levine; Virginia M. Klimek
Therapy-related myelodysplastic syndromes and acute myelogenous leukemia comprise a poor-risk subset of myelodysplastic syndromes and acute myelogenous leukemia. Large-scale mutation profiling efforts in de novo myelodysplastic syndromes have identified mutations that correlate with clinical features, but such mutations have not been investigated in therapy-related myelodysplastic syndromes and acute myelogenous leukemia. Genomic DNA from 38 patient samples were subjected to high throughput polymerase chain reaction and sequenced for TP53, TET2, DNMT3A, ASXL1, IDH1, IDH2, EZH2, EED, SUZ12, RBBP4, SRSF2, U2AF35, and SF3B1. We identified somatic mutations in 16 of 38 (42%) patients. TP53 mutations were the most common lesion, detected in 8 of 38 (21%) patients, followed by TET2 in 4 of 38 (10.5%). Cases with a TP53 mutation or loss of the TP53 locus had a worse overall survival compared to those with wild-type TP53 (8.8 vs. 37.4 months; P=0.0035).
Cancer Cell | 2016
Satoshi Inoue; Wanda Y. Li; Isabel Beerman; Andrew J. Elia; Sean C. Bendall; François Lemonnier; Ken Kron; David W. Cescon; Zhenyue Hao; Evan F. Lind; Naoya Takayama; Aline C. Planello; Shu Yi Shen; Alan H. Shih; Dana M. Larsen; Qinxi Li; Bryan E. Snow; Andrew Wakeham; Jillian Haight; Chiara Gorrini; Christian Bassi; Kelsie L. Thu; Kiichi Murakami; Alisha R. Elford; Takeshi Ueda; Kimberly Straley; Katharine E. Yen; Gerry Melino; Luisa Cimmino; Iannis Aifantis
Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia.
Seminars in Oncology | 2011
Alan H. Shih; Ross L. Levine
Myelodysplastic syndromes (MDS) are a group of clonal hematopoetic disorders marked by ineffective hematopoiesis, peripheral cytopenias, and an increased risk of transformation to acute myeloid leukemia. Multiple processes govern hematopoietic progenitor proliferation and natural differentiation into mature myeloid elements. Molecular events that disrupt any of these processes have the potential to lead to ineffective hematopoiesis and an MDS phenotype. Recent advances in genomic analysis have identified a number of new genes that may be involved. The molecular description of MDS will lead to better understanding, classification, and treatment of this disease.
Cancer Discovery | 2017
Alan H. Shih; Cem Meydan; Kaitlyn Shank; Francine E. Garrett-Bakelman; Patrick S. Ward; Andrew M. Intlekofer; Abbas Nazir; Eytan M. Stein; Kristina M. Knapp; Jacob Glass; Jeremy Travins; Kim Straley; Camelia Gliser; Christopher E. Mason; Katharine E. Yen; Craig B. Thompson; Ari Melnick; Ross L. Levine
Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2 Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.Significance: AMLs with mutations in TET2 or IDH2 are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response and can be used to inform mechanism-based combination therapy. Cancer Discov; 7(5); 494-505. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Yen et al., p. 478This article is highlighted in the In This Issue feature, p. 443.
Journal of Experimental Medicine | 2016
Megan Hatlen; Kanika Arora; Vladimir Vacic; Ewa A. Grabowska; Willey Liao; Bridget Riley-Gillis; Dayna Oschwald; Lan Wang; Jacob E. Joergens; Alan H. Shih; Franck Rapaport; Shengqing Gu; Francesca Voza; Takashi Asai; Benjamin G. Neel; Michael G. Kharas; Mithat Gonen; Ross L. Levine; Stephen D. Nimer
Hatlen et al. provide an integrative analysis of the mutational landscape of mouse and human AML and identify functionally relevant cooperation between AML1-ETO and PTPN11 D61Y. Based on these findings, they generate a novel mouse model of t(8;21)+ AML.