Jason Cheng, MD, PhD
Assitant Professor, Department of Pathology, University of Chicago
2014 Young Investigator Award – 2016 Interim Report

My research focuses on Epigenetics in myeloid neoplasms such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). “Epigenetics” refers to modifications of DNA, DNA-associated proteins, and/or RNA interference that alter chromatin structure and gene expression, while the DNA sequence remains unchanged. I focus my study on Epigenetics in MDS and AML because MDS and AML are common hematologic malignancies with poor prognosis, especially in older patients. Drugs that target various components of the epigenetic machinery have proven to be effective treatments for patients with MDS and AML. However, only some MDS/AML patients respond to such drugs, and the mechanisms underlying the selectivity and efficacy of epigenetic drugs in these patients are unknown. Therefore, there is an urgent clinical need for development of new technologies to identify patients who would benefit from epigenetic drug treatment and more effective drugs for MDS and AML. The biggest barrier to effective therapy is a lack of clear understanding as to how disruption of epigenetic regulation leads to development of MDS and AML, and how epigenetic-targeting drugs selectively work in some patients with MDS and AML. To address these questions, we proposed a novel working model/central hypothesis based on our preliminary data. Our working model/central hypothesis is that altered interactions between lineage-determining transcription factors and chromatin modifiers lead to the formation of distinct locus-specific, drug-sensitive chromatin structures in MDS/AML subtypes. We outlined three Specific Aims to elucidate the interacting domains/factors in the drug-sensitive chromatin structures in MDS/AML and to the interacting domains/factors to reprogram leukemia cells for more effective epigenetic therapy in MDS and AML.

Progress:

Thanks to the Young Investigator Award provided by the Cancer Research Foundation, my research projects have been progress very well. We have obtained some very exciting new data that further support our central hypothesis of disease-associated, drug-sensitive chromatin structures in MDS/AML. We are currently moving forward the projects to elucidate the details of such chromatin structures and to develop novel chromatin structure-based diagnostics and therapeutics. These new data also provide much needed evidence to support new grant applications, which are currently in the process of submission. The following are the published and pending research findings from the project supports by the YIA.

Peer reviewed publications:

Cheng JX, Yue MM, Li Y, Anastasi J, Shen JQ, Dou Y, Larson, RA, Vardiman, JW. Lineage-specific interaction and recruitment of TET2, DNMT1 and EZH2 determine differential drug-responses in leukaemias. Under review by Nature Communications.

Aslam MN, McClintock S, Khan SP, Perone P, Allen R, Ouillette PD, Dame MK, Cheng JX, Kunkel SL, Varani J. MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy. Anticancer Drugs. 2015 May 14.

Abstracts supported by this award support:

1. Li, Y., Yue, M., Anastasi, J., Yue, M., Shen, Q.J., Dou, Y., Larson, R.A., Vardiman, J.W. Cheng, J.X. Epigenetic modifying drugs inhibit MDS/AML cell growth through selective disruption of the interactions between lineage-determining transcription factors and DNA/histone modifiers. The 57th Annual Meeting of American Society of Hematology. Orlando, F.L., USA, 2015.

2. Cloe, A., Johnson, D., VanSlambrouck, C., Cheng, J. X. AXL: A Potential Biomarker in the Progression of Monocytic Leukemia. Boston, M.A., USA. The Annual Meeting of United States and Canadian Academy of Pathology (USCAP).

3. Cheng, J.X., Anastasi, J., Yue, M., Shen, Q.J., Larson, R.A., Vardiman, J.W. Identifying distinct differentiation/lineage-specific, drug-sensitive chromatin structures and the underlying novel mutations in MDS and AML. Platform presentation. The 13th International Symposium on Myelodysplastic Syndromes. Washington D.C., USA, 2015.

4. Cheng, J.X., Anastasi, J., Vardiman, J.W., Distinct Chromatin Conformations of PU.1 Dictate Differential Drug Responses in Two Different Types of Leukemia Cells: Implications in Effective Epigenetic Therapy in Leukemia. Platform presentation. USCAP 2014.

Department of Pathology, University of Chicago
2015 Young Investigator Award – 2017 Final Report

My research focuses on Epigenetics in myeloid neoplasms such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). “Epigenetics” refers to modifications of DNA, DNA-associated proteins, and/or RNA interference that alter chromatin structure and gene expression, while the DNA sequence remains unchanged. MDS and AML are common hematologic malignancies with poor prognosis, especially in older patients. Drugs that target various components of the epigenetic machinery have proven to be effective treatments for patients with MDS and AML. However, only some MDS/AML patients respond to such drugs, and the mechanisms underlying the selectivity and efficacy of epigenetic drugs in these patients are unknown. Therefore, there is an urgent clinical need for development of new technologies to identify patients who would benefit from epigenetic drug treatment and more effective drugs for MDS and AML. The biggest barrier to effective therapy is a lack of clear understanding how disruption of epigenetic regulation leads to development of MDS and AML and how epigenetic-targeting drugs selectively work in some patients with MDS and AML. To address these questions, we proposed a novel working model/central hypothesis based on our preliminary data. Our working model/central hypothesis is that altered interactions between lineage-determining transcription factors and chromatin modifiers lead to the formation of distinct locus-specific, drug-sensitive chromatin structures in MDS/AML subtypes. We outlined three Specific Aims to elucidate the interacting domains/factors in the drug-sensitive chromatin structures in MDS/AML and to the interacting domains/factors to reprogram leukemia cells for more effective epigenetic therapy in MDS and AML.

Progress:

Thanks to the Young Investigator Award provided by the Cancer Research Foundation, my research projects have been progressing very well. We have obtained a large set of exciting new data that further support our central hypothesis of disease-associated, drug-sensitive chromatin structures in MDS/AML. Two abstracts from this work entitled “Bromodomain and Extra-Terminal Motif Proteins (BETs) Mediate 5-Azacitidine Resistance in Myeloid Leukemia through Recruitment of an Active RNA Polymerase II Complex” and “RNA m5C Methyltransferases and hnRNP K Mediate Lineage-Specific Chromatin Structures and Differential Responses in Leukemia” were selected as platform presentations at the ASH annual meeting in December of 2016. Our work provides a novel RNA/chromatin structure-based drug action mechanism for 5-AZA, a known DNA methyltransferase inhibitor. Moreover, our work demonstrates that RNA:m5C methyltransferases (RCMTs), such as NSUN3 and DNMT2, and BRD4/BET are involved in the response and resistance to 5-AZA. Currently, little is known about the functions of NSUN3 (and other RNA m5C methyltransferases). This study may lead to the clarification of the pathophysiologic roles of RCMTs and the identification of new therapeutic targets for leukemia and other diseases.

We are currently moving forward the projects to elucidate the details of such chromatin structures and to develop novel chromatin structure-based diagnostics and therapeutics. These new data also provide much needed evidence to support new grant applications, which are currently in the process of submission. The following are the published and pending research findings from the project supports by the YIA.

Peer reviewed publications:

Aslam MN, McClintock S, Khan SP, Perone P, Allen R, Ouillette PD, Dame MK, Cheng JX, Kunkel SL, Varani J. MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy. Anticancer Drugs 26:763-73, 2015.

Yuan Li, Ming Yue, John Anastasi, Jeffery Q Shen, Yali Dou, Richard A. Larson, James W. Vardiman and Jason X. Cheng. Epigenetic Modifying Drugs Inhibit MDS/AML Cell Growth through Selective Disruption of the Interactions Between Lineage-Determining Transcription Factors and DNA/Histone Modifiers. Blood 2015 126:3853 (abstract).

Li Chen, Yuan Li, Ming Yue, Adam Cloe, Michelle M. Le Beau, Chuan He, Richard A. Larson, James W. Vardiman and Jason X. Cheng. Bromodomain and Extra-Terminal Motif Proteins (BETs) Mediate 5-Azacitidine Resistance in Myeloid Leukemia through Recruitment of an Active RNA Polymerase II Complex. Blood 2016 128:746 (abstract).

Adam Cloe, Li Chen, Yuan Li, Hongtao Liu and Jason X. Cheng. Identification of Specific Hnrnps As Novel Therapeutic Targets and Responsive Indicators of KPT330 (selinexor) in Leukemia. Blood 2016 128:1657 (abstract).

Angela Stoddart, Jianghong Wang, Chunmei Hu, Anthony A. Fernald, Elizabeth M. Davis, Jason X. Cheng and Michelle M. Le Beau. Inhibition of Canonical WNT Signaling in the Bone Marrow Niche Prevents the Development of Disease in a Mouse MDS Model with Apc Haploinsufficiency. Blood 2017, in press.

Yuan Li, Li Chen, Adam Cloe, Ming Yue, Michelle Le Beau, Richard A. Larson, Chuan He, John Anastasi, James W. Vardiman and Jason X. Cheng. RNA/m5C methyltransferase/hnRNPK Mediate Chromatin Organization and 5-Azacytidine Response in Leukemia. In the review of Nature Communication.

Li Chen, Adam Cloe, Michelle Le Beau, Richard A. Larson, James W. Vardiman and Jason X. Cheng. RNA/m5C methyltransferases and BRD4/BET Mediate 5-Azacitidine Resistance through Active RNA Polymerase II. In preparation.

Adam Cloe, Li Chen, Megan Parilla, HongTao Liu and Jason X. Cheng. Identification of Specific hnRNPs As Novel Therapeutic Targets and Responsive Indicators of KPT330 (selinexor) in Leukemia. In preparation.