Acute Myeloid Leukemia (AML) is adults’ most common acute leukemia. AML prognosis and overall survival decline in patients older than 60 and in patients who develop disease relapse after initial treatments. Our main research goal is to understand molecular and epigenetic mechanisms responsible for AML disease phenotypes. Through this aim, in the long-term, findings will help identify novel therapeutic targets in AML.
We investigate these questions by studying samples from AML patients and functional validations in vitro and in vivo models. Epigenetic (DNA methylation, gene expression, and chromatin assays) and molecular and cellular biology techniques are implemented to study how aberrant expression of specific genes contribute to abnormal cellular phenotypes and leukemogenesis. Previous studies have determined that AML progression (from disease diagnosis to relapse) is characterized by significant epigenetic plasticity and differentially expressed genes. Studies are being pursued to identify genes affected by the epigenetic changes observed and how their function contributes to the malignant phenotype.
C Duy, M Teater , F Garrett-Bakelman , T Lee, C Meydan , J Glass , M Li, J Hellmuth , H Mohammad , K Smitheman , A Shih , O Abdel-Wahab , M Tallman , M Guzman , D Muench , H Grimes , G Roboz , R Kruger , C Creasy , E Paietta , R Levine , M Carroll , A Melnick, Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML, 2019; Cancer Discovery. 9(7) 872-889. PMID: | PMCID: 31076479
G Martin , S Chakraborty , A Desrichard , S Chung , C Woolthuis , W Hu , I Berezniuk , F Garrett-Bakelman, J Hamann , D Devlin , T Chan , C Park , CD97 is a Critical Regulator of Acute Myeloid Leukemia Stem Cell Function, 2019; JEM. 216(10) 2362-2377. PMID: | PMCID: PMC6781010
H Kunimoto , C Meydan , A Nazir , J Whitfield , K Shank , F Rapaport , R Maher , E Pronier , S Meyer , F Garrett-Bakelman , M Tallman , A Melnick , R Levine ., A Shih , Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity, 2018; Cancer Cell. 33(1) 44-59.e8. PMID: | PMCID: PMC5760367
Shih AH, Meydan C, Shank K, Garrett-Bakelman FE, Ward PS, Intlekofer AM, Nazir A, Stein EM, Knapp K, Glass J, Travins J, Straley K, Gliser C, Mason CE, Yen K, Thompson CB, Melnick A, Levine RL, Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia., 2017; Cancer discovery. 7(5) 494-505. PMID: 28193779 | PMCID: PMC5413413
Glass J, Hassane DC, Wouters B, Kunimoto H, Avellino R, Garrett-Bakelman FE, Guryanova OA, Bowman R, Redlich S, Intlekofer A, Meydan C, Qin T, Fall MP, Alonso A, Guzman ML, Valk PJ, Thompson CB, Levine RL, Elemento O, Delwel R, Melnick A, Figueroa ME, Epigenetic Identity in AML Depends on Disruption of Non-promoter Regulatory Elements and is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers., 2017; Cancer discovery. () . PMID: 28408400
Kunimoto H, McKenney AS, Meydan C, Shank K, Nazir A, Rapaport F, Durham B, Garrett-Bakelman FE, Pronier E, Shih AH, Melnick A, Chaudhuri J, Levine RL, Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells., 2017; Blood. 129(13) 1779-1790. PMID: 28077417 | PMCID: PMC5374286
Chung SS, Eng WS, Hu W, Khalaj M, Garrett-Bakelman FE, Tavakkoli M, Levine RL, Carroll M, Klimek VM, Melnick AM, Park CY, CD99 is a therapeutic target on disease stem cells in myeloid malignancies., 2017; Science translational medicine. 9(374) . PMID: 28123069
Li S, Garrett-Bakelman FE, Chung SS, Sanders MA, Hricik T, Rapaport F, Patel J, Dillon R, Vijay P, Brown AL, Perl AE, Cannon J, Bullinger L, Luger S, Becker M, Lewis ID, To LB, Delwel R, Löwenberg B, Döhner H, Döhner K, Guzman ML, Hassane DC, Roboz GJ, Grimwade D, Valk PJ, D’Andrea RJ, Carroll M, Park CY, Neuberg D, Levine R, Melnick AM, Mason CE, Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia., 2016; Nature medicine. 22(7) 792-9. PMID: 27322744 | PMCID: PMC4938719
Garrett-Bakelman FE, Sheridan CK, Kacmarczyk TJ, Ishii J, Betel D, Alonso A, Mason CE, Figueroa ME, Melnick AM, Enhanced reduced representation bisulfite sequencing for assessment of DNA methylation at base-pair resolution., 2015; Journal of visualized experiments: JoVE. (96) e52246. PMID: 25742437 | PMCID: PMC4354670
Akalin A, Garrett-Bakelman FE, Kormaksson M, Busuttil J, Zhang L, Khrebtukova I, Milne TA, Huang Y, Biswas D, Hess JL, Allis CD, Roeder RG, Valk PJ, Löwenberg B, Delwel R, Fernandez HF, Paietta E, Tallman MS, Schroth GP, Mason CE, Melnick A, Figueroa ME, Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia., 2012; PLoS genetics. 8(6) e1002781. PMID: 22737091 | PMCID: PMC3380828