Epigenetic Alterations and Targeted Therapies in North American ATLL

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Principal Investigator: Bihui Hilda Ye
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $514,837
Funding agency: National Cancer Institute

PROJECT SUMMARY/ABSTRACT
Adult T-cell leukemia/lymphoma (ATLL) is a disease of malignant CD4+ T cells that develops in human T-
lymphotropic virus-1 (HTLV-1) carriers. The 3-yr overall survival is an abysmal 25% even when managed with
the most aggressive chemotherapy. No outcome-changing targeted treatment currently exists. Thus, improved
understanding of pathogenesis and novel therapeutic strategies are urgently needed. We and others have shown
that ATLLs diagnosed in the Japanese (J-ATLL) and North American (NA-ATLL) patients have very different
clinical behavior, with the North American variant characterized by a higher rate of chemo-refractory disease and
worse prognosis. Recently, we performed the first targeted exon sequencing analysis in 30 patients seen at our
center and discovered significantly more mutations in genes controlling epigenetic modifications and fewer
mutations in the TCR/NF-kappaB signaling pathways than the Japanese ATLLs. Strikingly, the frequency of
EP300 mutations in our patient cohort (20%) was about 4 times that seen in the Japanese cohort (5.7%). One
of the transcription factors that can be acetylated by p300 is BCL6, a transcription repressor that critically controls
many functional aspects of mature B and T cells. We have discovered for the first time that BCL6 is expressed
in primary ATLL samples and ATLL cell lines. Interestingly, NA-ATLL cell lines are notably more sensitive than
J-ATLL cell lines to BCL6 inhibition. Additional experiments suggest that in NA-ATLL cells, BCL6 plays an
essential role enabling survival of NA-ATLL cells as they cope with elevated DNA replication stress during S-
phase of the cell cycle. Supporting the concept that the S-phase is an Achilles’ heel of NA-ATLL cells, these cells
but not the J-ATLL cells are exquisitely sensitive to a PARP inhibitor, Olaparib. These findings support our
working hypothesis that dysregulated epigenetic program is a central feature of NA-ATLL biology and that
attenuated p300 activity combined with a unique role of BCL6 in S-phase programs provides a novel opportunity
for therapeutic targeting. The following three specific aims are proposed to test this hypothesis.
Aim 1. Elucidate the mechanisms by which p300 regulates chromatin and gene expression in NA-ATLL.
Aim 2. Characterize the roles of p300 and BCL6 as regulators of DNA replication program and genome stability
in NA-ATLL.
Aim 3. Determine the mechanistic basis of PARPi sensitivity and design therapeutic strategies to target the S-
phase vulnerabilities of NA-ATLL.

Terms: <5-Azadeoxycytidine><5-deoxyazacytidine><ATLL><Acetylation><Acetyltransferase><Adult T-Cell Leukemia><Adult T-Cell Leukemia-Lymphoma Virus I><Adult T-Cell Leukemia/Lymphoma><Adult T-Cell Lymphoma/Leukemia><American><Antioncogene Protein p53><Assay><Attenuated><B blood cells><B cell><B cell lymphoma 6><B cells><B-Cell CLL/Lymphoma-6 Gene><B-Cells><B-Lymphocytes><B-cell><BCL5><BCL6><BCL6 gene><Basal Transcription Factor><Basal transcription factor genes><Behavior><Bioassay><Biological Assay><Biology><Breast Cancer Cell><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cancers><Caribbean><Caribbean Sea Region><Caribbean region><Cell Body><Cell Cycle><Cell Division Cycle><Cell Line><CellLine><Cells><Cellular Tumor Antigen P53><Chemoresistance><Chromatin><Clinical><Clinical Management><Clonal Expansion><Cys-His2 Zinc Finger Transcription Factor Gene><DNA Damage><DNA Damage Repair><DNA Injury><DNA Methylation><DNA Repair><DNA Replication><DNA Synthesis><DNA biosynthesis><DNA replication fork><Decitabine><Defect><Deoxyazacytidine><Dezocitidine><Diagnosis><Disease><Disorder><Drosophila Homolog of NOTCH 1><Drug Targeting><E1A Binding Protein p300><E1A-associated p300 protein><EP300><EP300 gene><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Exons><Frequencies><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome Instability><Genome Stability><Genomic Instability><Genomic Stability><Genomics><HTLV-1><HTLV-I><HTLV1><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Histones><Hospitals><Human T-Cell Leukemia Virus I><Human T-lymphotropic virus 1><Ig Genes><Immunoglobulin Enhancer-Binding Protein><Immunoglobulin Genes><Japan><Japanese><KAT3B><L-Lysine><LAZ-3 Gene><LAZ3><Latin American><Lymphoma cell><Lysine><Lytotoxicity><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Tumor><Mature B-Cell><Mature B-Lymphocyte><Mature T-Cell><Mature T-Lymphocyte><Modification><Molecular><Mutate><Mutation><NF-kB><NF-kappa B><NF-kappaB><NFKB><NOTCH1><NOTCH1 gene><North America><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Oncoprotein p53><Outcome><P53><PARP Inhibitor><PARP-1 inhibitor><PARPi><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Pattern><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Physiologic><Physiological><Play><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) polymerase 1 inhibitor><Pre-Clinical Model><Preclinical Models><Process><Prognosis><Protein TP53><Refractory Disease><Reporting><Role><S Period><S phase><Sampling><Signal Pathway><Strains Cell Lines><Synthesis Period><Synthesis Phase><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TAN1><TP53><TP53 gene><TRP53><Testing><Therapeutic><Time><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription Repressor><Transcription factor genes><Transcriptional Repressor><Translocation-Associated NOTCH Homolog><Tumor Protein p53><Tumor Protein p53 Gene><Type I Human T-Lymphotropic Virus><Unscheduled DNA Synthesis><Variant><Variation><Virus-HTLV-I><West Indies Region><ZNF51><ZNF51 Gene><Zinc Finger Protein 51 Gene><attenuate><attenuates><blood cell formation><breast tumor cell><c myc><c-myc Genes><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><cmyc><cohort><coping><cultured cell line><cytotoxicity><design><designing><determine efficacy><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epigenetic regulation><epigenetically><evaluate efficacy><examine efficacy><experience><experiment><experimental research><experimental study><experiments><genetic repressor><genome mutation><genome scale><genome-wide><genomewide><histone acetyltransferase p300><homologous recombination><human T cell lymphoma virus I><human T cell lymphoma virus type I><human T cell lymphotropic virus  1><human T cell lymphotropic virus type 1><human T lymphotropic virus I><human T-cell leukemia virus type 1><improved><in vitro activity><kappa B Enhancer Binding Protein><malignancy><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><nuclear factor kappa beta><p300><p300 E1A-associated coactivator><p300 protein><p300-CBP coactivator><p300/CBP proteins><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><pre-clinical><preclinical><programs><protein p53><replication fork><replication stress><response><social role><targeted agent><targeted drug therapy><targeted drug treatments><targeted sequencing><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><thymus derived lymphocyte><transcription factor><treatment strategy><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog>