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Sunderland Repository records the research produced by the University of Sunderland including practice-based research and theses.

Abstract 224: Histone H3 Methylation Mediates All-Trans-Retinoic Acid Responsiveness in Acute Myeloid Leukemia.

Schenk, Tino, Göllner, Stefanie, Chen, Weihsu Claire, Howell, Louise, Jin, Liqing, Hebestreit, Katja, Klein, Hans-Ulrich, Burnett, Alan K, Mills, Ken I., Marton, Laurence, Casero, Robert, Woster, Patrick, Dugas, Martin, Wang, Jean C.Y., Dick, John E., Müller-Tidow, Carsten, Petrie, Kevin and Zelent, Arthur (2011) Abstract 224: Histone H3 Methylation Mediates All-Trans-Retinoic Acid Responsiveness in Acute Myeloid Leukemia. Blood, 118 (21). p. 224. ISSN 0006-4971

Item Type: Article


During hematopoiesis, all-trans-retinoic acid (ATRA), a natural derivative of vitamin A, has been shown to induce both myelomonocytic progenitor/stem cell differentiation and self-renewal. Although these opposing effects are likely to be partly due to developmental differences, it has been shown that pro- and anti-differentiation effects of ATRA are mediated by distinct retinoic acid receptor isotypes (RARα and RARγ, respectively). With the exception of acute promyelocytic leukemia (APL), ATRA treatment as a single agent has not been successful in other types of acute myeloid leukemia (AML). We have previously hypothesized that one of the underlying reasons for poor response of non-APL AML to ATRA (pan-RAR agonist) is aberrant expression and/or activities of RAR isotypes favoring RARγ and cell growth versus differentiation. Consistently, we have reported that expression of RARα isoforms, particularly ATRA-inducible RARα2, are down-regulated in AML (Blood. 2008; 111:2374). Epigenetic analysis of patient samples revealed that relative to normal CD33+ cells, the loss of RARα2 in AML is associated with a diminution in levels of histone histone H3 lysine 4 dimethylation (H3K4me2) on the ATRA-responsive RARA2 promoter (a modification associated with transcriptional activation). Interestingly, the H3K4me1/me2 demethylase LSD1/KDM1 (AOF2) is highly expressed in AML patients ( A number of small molecules that target this enzyme (LSD1i) are in development and, collectively, these data predict that the use of LSD1i will facilitate induction of expression of genes that are required for differentiation of AML cells. In this study we used tranylcypromine (TCP, a monoamine oxidase used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively), which functions a time-dependent, mechanism-based inhibitor of LSD1.
Here we show that TCP unlocked the ATRA-driven therapeutic differentiation response in non-APL AML cell lines including the TEX cell line, which is derived from primitive human cord blood cells immortalized by expression of the TLS-ERG oncogene. TEX cells are >90% CD34+, respond poorly to ATRA and mimic features of primary human AML and leukemia initiating cells (Leukemia. 2005; 19:1794). Consistent with this, ATRA/TCP treatment increased differentiation in primary patient samples. ATRA alone had in general only small effects in primary AML samples and TCP showed minimal activity in most cases. Furthermore, shRNA-mediated knockdown of LSD1 confirmed a critical role for this enzyme in blocking the ATRA response in AML cells.
The effects of ATRA/TCP on AML cell maturation were paralleled by enhanced induction of genes associated with myelomonocytic differentiation, including direct ATRA targets. LSD1i treatment did not lead to an increase in genome-wide H3K4me2, but did increase H3K4 dimethylation of myelomonocytic differentiation-associated genes. Importantly, treatment with ATRA/TCP dramatically diminished the clonogenic capacity of AML cells in vitro and engraftment of cells derived from AML patients in vivo, suggesting that ATRA/TCP may also target leukemic stem cells. These data strongly suggest that LSD1 may, at least in part, contribute to AML pathogenesis by inhibiting the normal function of ATRA in myelomonocytic development and pave the way for effective differentiation therapy of AML.

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Uncontrolled Keywords: histone h3, leukemia, myelocytic, acute, methylation, tretinoin, enzymes, leukemia, acute promyelocytic leukemia, agonists, anti-anxiety agents, antidepressive agents
Depositing User: Kevin Petrie


Item ID: 15817
Identification Number:
ISSN: 0006-4971
Official URL:

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ORCID for Kevin Petrie: ORCID iD

Catalogue record

Date Deposited: 22 Mar 2023 15:40
Last Modified: 22 Mar 2023 15:40


Author: Kevin Petrie ORCID iD
Author: Tino Schenk
Author: Stefanie Göllner
Author: Weihsu Claire Chen
Author: Louise Howell
Author: Liqing Jin
Author: Katja Hebestreit
Author: Hans-Ulrich Klein
Author: Alan K Burnett
Author: Ken I. Mills
Author: Laurence Marton
Author: Robert Casero
Author: Patrick Woster
Author: Martin Dugas
Author: Jean C.Y. Wang
Author: John E. Dick
Author: Carsten Müller-Tidow
Author: Arthur Zelent

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine


Sciences > Biomedical Sciences

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