Integrative single‐cell expression and functional studies unravels a sensitization to cytarabine‐based chemotherapy through HIF pathway inhibition in AML leukemia stem cells

Abstract

Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy‐resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML‐LSCs and may represent a therapeutic target to sensitize AML‐LSCs to chemotherapy. Here, we identify HIFhigh and HIFlow specific AML subgroups (inv(16)/t(8;21) and MLLr, respectively) and provide a comprehensive single‐cell expression atlas of 119,000 AML cells and AML‐LSCs in paired diagnostic‐relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML‐LSCs compared with more differentiated AML cells but is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard‐of‐care chemotherapy to impair AML growth and to substantially eliminate AML‐LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell‐driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy‐based approaches to specifically eliminate AML‐LSCs.

From hypoxia single‐cell gene signatures to HIF targeting of AML leukemic stem cells

“…Their data support the potential of targeting hypoxia-induced gene regulation in leukemic stem cells (LSC) in AML. 2 Oxygen homeostasis is transcriptionally regulated by a family of hypoxia-inducible factors (HIF) that act as transcriptional activators and repressors. Heterodimeric HIFs are formed by a constitutively expressed HIF1β subunit (encoded by ARNT) and a HIF1/2/3α (encoded by HIF1A, EPAS1, HIF3A, respectively).…”

“…Collectively, Velasco et al unraveled the LSC transcriptomes and particularly hypoxia-regulated genes at the single-cell level from AML patients at diagnosis and relapse and provided experimental evidence of synergistic antileukemic activity of small molecule HIF inhibitors and Ara-C in vitro and in vivo. 2 With the development of easy-to-perform experimental platforms, the number of studies that report AML transcriptomes at the single-cell level is rapidly increasing. 4 In their work, Velasco et al revealed the gene expression signatures of over 100,000 primary blasts from AML patients of the most prevalent genetic subgroups.…”