American Association for Cancer Research
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00085472can190274-sup-215950_2_supp_5740901_px15zv.pdf (210.76 kB)

Figure S1 from Diminished AHR Signaling Drives Human Acute Myeloid Leukemia Stem Cell Maintenance

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journal contribution
posted on 2023-03-31, 02:44 authored by Michelle Ly, Stefan Rentas, Ana Vujovic, Nicholas Wong, Steven Moreira, Joshua Xu, Nicholas Holzapfel, Sonam Bhatia, Damian Tran, Mark D. Minden, Jonathan S. Draper, Kristin J. Hope

This figure displays the elevated expression of MSI2 in LSCs and depicts the reduced leukemic burden in xenografts upon MSI2 knockdown

Funding

Ontario Institute of Cancer Research Investigator Award

CIHR

CIHR PhD Scholarship

History

ARTICLE ABSTRACT

Eliminating leukemic stem cells (LSC) 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 pathologic 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 versus 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. The AHR pathway is suppressed in leukemic stem cells (LSC), therefore activating AHR signaling is a potential therapeutic option to target LSCs and to treat acute myeloid leukemia.