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. SIGNIFICANCE: 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.
Highlights
Acute myeloid leukemia (AML) is initiated by driver gene mutations in hematopoietic stem or progenitor cells (HSPC) that give rise to leukemic stem cells (LSC), characterized by extensive self-renewal activity and a limited differentiation capacity that enables their production of large numbers of immature myeloid cells [1,2,3]
aryl hydrocarbon receptor (AHR) signaling is attenuated in LSCs In exploring differential gene expression that may contribute to LSC function, we examined published transcriptional profiling from the validated LSCþ and LSC-devoid (LSCÀ) fractions of 78 patient samples [6]
Within this dataset, we observed that MSI2, a regulator of asymmetric division and numb translation in mouse AML [24, 25] and which we have shown mediates repression of AHR signaling in human hematopoietic stem cells (HSC) to promote their expansion [15], is transcriptionally elevated 1.6-fold in LSCþ versus LSCÀ samples
Summary
Acute myeloid leukemia (AML) is initiated by driver gene mutations in hematopoietic stem or progenitor cells (HSPC) that give rise to leukemic stem cells (LSC), characterized by extensive self-renewal activity and a limited differentiation capacity that enables their production of large numbers of immature myeloid cells [1,2,3]. Because LSCs drive disease initiation and relapse [4], effective long-lasting antileukemic treatments are dependent on promoting LSC death or terminal differentiation. Meeting this critical goal has been challenging due to the limited understanding of the molecular pathways that underpin the human AML-LSC self-renewal program. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). These studies suggest that there are fundamental molecular mechanisms characteristic of HSCs that may be exploited to drive the active self-renewal and impaired differentiation of LSCs. The challenge, given the reliance of LSCs on mechanisms utilized for normal HSC function, is to define selective means to disrupt these pathways preferentially in LSCs, so that HSCs are spared
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