Diminished AHR signaling drives human acute myeloid leukemia stem cell maintenance

Ly, M., Rentas, S., Vujovic, A., Wong, N., Moreira, S., Xu, J., Holzapfel, N., Bhatia, S., Tran, D., Minden, M. D., Draper, J. S., Hope, K. J. (September 2019) Diminished AHR signaling drives human acute myeloid leukemia stem cell maintenance. Cancer Res. ISSN 0008-5472

Abstract

Eliminating leukemic stem cells (LSCs) is a sought after therapeutic paradigm for the treatment of acute myeloid leukemia (AML). While repression of aryl hydrocarbon receptor (AHR) signaling has been shown to promote short term maintenance of primitive AML cells in culture, no work to date has examined whether altered AHR signaling plays a pathological role in human AML or whether it contributes at all to endogenous LSC function. Here we show AHR signaling is repressed in human AML blasts and preferentially downregulated in LSC-enriched populations within leukemias. A core set of AHR targets are uniquely repressed in LSCs across diverse genetic AML subtypes. In vitro and in vivo administration of the specific AHR agonist FICZ significantly impaired leukemic growth, promoted differentiation and repressed self-renewal. Furthermore, LSCs suppressed a set of FICZ-responsive AHR-target genes that function as tumor suppressors and promoters of differentiation. FICZ stimulation did not impair normal hematopoietic stem and progenitor (HSPC) function, and failed to upregulate a prominent LSC-specific AHR target in HSPCs suggesting that differential mechanisms govern FICZ-induced AHR signaling manifestations in HSCs vs LSCs. Altogether, this work highlights AHR signaling suppression as a key LSC-regulating control mechanism and provides proof of concept in a preclinical model that FICZ-mediated AHR pathway activation enacts unique transcriptional programs in AML that identify it as a novel chemotherapeutic approach to selectively target human LSCs.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > acute myeloid leukemia organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > differentiation diseases & disorders > cancer > cancer types > leukemia organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > tissues types and functions diseases & disorders > cancer > cancer types
CSHL Authors:	Bhatia, Sonam
Communities:	CSHL labs > Spector lab
Depositing User:	Matthew Dunn
Date:	13 September 2019
Date Deposited:	17 Sep 2019 16:34
Last Modified:	02 Feb 2024 17:12
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38409

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