Epigenetic Drug Combination Induces Remission in Mouse Xenograft Models of Pediatric Acute Myeloid Leukemia

Overview

Journal Leuk Res

Date 2017 May 16

PMID 28505595

Citations 9

Authors

Anilkumar Gopalakrishnapillai

E Anders Kolb

Suzanne M McCahan

Sonali P Barwe

Affiliations

Soon will be listed here.

Abstract

Aberrations in epigenetic modifications contribute to leukemogenesis in childhood acute myeloid leukemia (AML). We combined DNA hypomethylating agent azacitidine with histone deacetylase inhibitor panobinostat in preclinical models of childhood AML. Synergistic cytotoxic effect upon treatment with azacitidine and panobinostat with combination indices <1.0 was observed. Azacitidine and panobinostat increased median survival by 26 and 6days respectively in MV4;11 xenografted mice. Mice treated with both drugs showed a drastic reduction in leukemic burden leading to complete remission sustained for the duration of the experimental period lasting more than 519days. Reduced leukemic burden and prolonged survival was also observed in AML-193 xenografted mice treated with azacitidine-panobinostat combination. Differential gene expression profiling was performed on AML cells treated with azacitidine, panobinostat or azacitidine-panobinostat combination. Functional mapping of transcripts uniquely regulated by the azacitidine-panobinostat combination in MV4;11 cells identified p53 as an upstream regulator. A comparison of the uniquely modulated transcripts by azacitidine-panobinostat combination in MV4;11 cells versus AML-193 and THP-1 cells, bearing mutated p53, also revealed p53 as the topmost upstream regulator. Finally, expression of mutant p53 in MV4;11 cells reduced sensitivity to azacitidine-panobinostat combination, suggesting that p53 may be a predictor of response to epigenetic therapy in pediatric AML.

Citing Articles

Bone Marrow Microenvironment-Induced Chemoprotection in Rearranged Pediatric AML Is Overcome by Azacitidine-Panobinostat Combination.

Lehner K, Gopalakrishnapillai A, Kolb E, Barwe S Cancers (Basel). 2023; 15(12).

PMID: 37370721 PMC: 10296268. DOI: 10.3390/cancers15123112.

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts.

Barwe S, Huang F, Kolb E, Gopalakrishnapillai A J Clin Med. 2022; 11(7).

PMID: 35407531 PMC: 8999576. DOI: 10.3390/jcm11071923.

Immunotherapeutic Targeting of Mesothelin Positive Pediatric AML Using Bispecific T Cell Engaging Antibodies.

Gopalakrishnapillai A, Correnti C, Pilat K, Lin I, Chan M, Bandaranayake A Cancers (Basel). 2021; 13(23).

PMID: 34885074 PMC: 8657033. DOI: 10.3390/cancers13235964.

Harnessing the Power of Induced Pluripotent Stem Cells and Gene Editing Technology: Therapeutic Implications in Hematological Malignancies.

Sidhu I, Barwe S, Pillai R, Gopalakrishnapillai A Cells. 2021; 10(10).

PMID: 34685678 PMC: 8534597. DOI: 10.3390/cells10102698.

Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy.

Conneely S, Stevens A Curr Oncol Rep. 2021; 23(2):16.

PMID: 33439382 PMC: 7806552. DOI: 10.1007/s11912-020-01009-3.

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