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bioRxiv · 10.1101/2022.03.02.482638

A comprehensive single-cell expression atlas of human AML leukemia-initiating cells unravels the contribution of HIF pathway and its therapeutic potential

Velasco-Hernandez, T.·Trincado, J. L.·Vinyoles, M.·Closa, A.·Gutierrez-Aguera, F.·Molina, O.·Rodriguez-Cortez, V. C.·Petazzi, P.·Beneyto-Calabuig, S.·Velten, L.·Romecin, P.·Casquero, R.·Abollo-Jimenez, F.·Diaz de la Guardia, R.·Lorden, P.·Bataller, A.·Lapillonne, H.·Stam, R. W.·Vives, S.·Torrebadell, M.·Fuster, J. L.·Bueno, C.·Eyras, E.·Heyn, H.·Menendez, P.
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Abstract

Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML), and is driven by rare therapy-resistant leukemia-initiating stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling keeps cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to AML-LSC function and chemoresistance and is a therapeutic target to sensitize AML-LSCs to chemotherapy. Here, we provide a comprehensive single-cell expression atlas (119,000 cells) of AML cells and AML-LSCs in paired diagnostic-relapse samples from risk-stratified patients with AML. The HIF/hypoxia pathway is attenuated in AML-LSCs compared with differentiated AML cells, but is enhanced when compared with healthy hematopoietic cells. Accordingly, chemical inhibition cooperates with standard-of-care chemotherapy to impair leukemogenesis, substantially eliminating AML-LSCs. These findings support the HIF pathway as a stem cell regulator in human AML, and reveal avenues for combinatorial targeted and chemotherapy-based approaches to specifically eliminate AML-LSCs.

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Velasco-Hernandez, T., Trincado, J. L., Vinyoles, M., Closa, A., Gutierrez-Aguera, F., Molina, O., Rodriguez-Cortez, V. C., Petazzi, P., Beneyto-Calabuig, S., Velten, L., Romecin, P., Casquero, R., Abollo-Jimenez, F., Diaz de la Guardia, R., Lorden, P., Bataller, A., Lapillonne, H., Stam, R. W., Vives, S., Torrebadell, M., Fuster, J. L., Bueno, C., Eyras, E., Heyn, H., Menendez, P.. 2022-03-04. A comprehensive single-cell expression atlas of human AML leukemia-initiating cells unravels the contribution of HIF pathway and its therapeutic potential. https://doi.org/10.1101/2022.03.02.482638

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