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Ref Type Journal Article
PMID (26837761)
Authors McGrath JP, Williamson KE, Balasubramanian S, Odate S, Arora S, Hatton C, Edwards TM, O'Brien T, Magnuson S, Stokoe D, Daniels DL, Bryant BM, Trojer P
Title Pharmacological Inhibition of the Histone Lysine Demethylase KDM1A Suppresses the Growth of Multiple Acute Myeloid Leukemia Subtypes.
Journal Cancer research
Vol 76
Issue 7
Date 2016 04 01
URL
Abstract Text Lysine-specific demethylase 1 (KDM1A) is a transcriptional coregulator that can function in both the activation and repression of gene expression, depending upon context. KDM1A plays an important role in hematopoiesis and was identified as a dependency factor in leukemia stem cell populations. Therefore, we investigated the consequences of inhibiting KDM1A in a panel of cell lines representing all acute myelogenous leukemia (AML) subtypes using selective, reversible and irreversible KDM1A small-molecule inhibitors. Cell models of AML, CML, and T-ALL were potently affected by KDM1A inhibition, and cells bearing RUNX1-RUNX1T1 (AML1-ETO) translocations were especially among the most sensitive. RNAi-mediated silencing of KDM1A also effectively suppressed growth of RUNX1-RUNX1T1-containing cell lines. Furthermore, pharmacologic inhibition of KDM1A resulted in complete abrogation of tumor growth in an AML xenograft model harboring RUNX1-RUNX1T1 translocations. We unexpectedly found that KDM1A-targeting compounds not only inhibited the catalytic activity of the enzyme, but evicted KDM1A from target genes. Accordingly, compound-mediated KDM1A eviction was associated with elevated levels of local histone H3 lysine 4 dimethylation, and increased target gene expression, which was further accompanied by cellular differentiation and induction of cell death. Finally, our finding that KDM1A inhibitors effectively synergize with multiple conventional as well as candidate anti-AML agents affords a framework for potential future clinical application. Cancer Res; 76(7); 1975-88. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
RN-1 RN-1 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
GSK690 KDM1A Inhibitor 12 GSK690 is a reversible inhibitor of KDM1A, which potentially reduces tumor cell growth (PMID: 26837761).
RN-1 KDM1A Inhibitor 12 RN-1 irreversibly inhibits KDM1A, potentially resulting in decreased tumor cell growth (PMID: 26837761).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown acute myeloid leukemia not applicable CPI-169 + RN-1 Preclinical - Cell culture Actionable In a preclinical study, RN-1 and CPI-169 demonstrated synergy in growth inhibition of several acute myeloid leukemia cell lines in culture (PMID: 26837761). 26837761
RUNX1 - RUNX1T1 acute myeloid leukemia sensitive GSK690 Preclinical - Cell culture Actionable In a preclinical study, GSK690 inhibited growth of acute myeloid leukemia cell lines harboring RUNX1-RUNX1T1 in culture (PMID: 26837761). 26837761
RUNX1 - RUNX1T1 acute myeloid leukemia sensitive RN-1 Preclinical - Cell line xenograft Actionable In a preclinical study, RN-1 inhibited growth of acute myeloid leukemia cell lines harboring RUNX1-RUNX1T1 in culture, and inhibited tumor growth in xenograft models (PMID: 26837761). 26837761
Unknown unknown acute myeloid leukemia not applicable Cytarabine + RN-1 Preclinical - Cell culture Actionable In a preclinical study, RN-1 and Cytosar-U (cytarabine) demonstrated synergy in growth inhibition of several acute myeloid leukemia cell lines in culture (PMID: 26837761). 26837761
Unknown unknown acute myeloid leukemia not applicable RN-1 + Tretinoin Preclinical - Cell culture Actionable In a preclinical study, RN-1 and Vesanoid (tretinoin) demonstrated synergy in growth inhibition of several acute myeloid leukemia cell lines in culture (PMID: 26837761). 26837761
Unknown unknown acute myeloid leukemia not applicable RN-1 Preclinical - Cell culture Actionable In a preclinical study, RN-1 inhibited growth of acute myeloid leukemia cell lines in culture (PMID: 26837761). 26837761
Unknown unknown chronic myeloid leukemia not applicable RN-1 Preclinical - Cell culture Actionable In a preclinical study, RN-1 inhibited growth of chronic myeloid leukemia cell lines in culture (PMID: 26837761). 26837761