Hif-1α Deletion May Lead to Adverse Treatment Effect in a Mouse Model of MLL-AF9-Driven AML

Summary: Relapse of acute myeloid leukemia (AML) remains a significant clinical challenge due to limited therapeutic options and poor prognosis. Leukemic stem cells (LSCs) are the cellular units responsible for relapse in AML, and strategies that target LSCs are thus critical. One proposed potential strategy to this end is to break the quiescent state of LSCs, thereby sensitizing LSCs to conventional cytostatics. The hypoxia-inducible factor (HIF) pathway is a main driver of cellular quiescence and a potential therapeutic target, with precedence from both solid cancers and leukemias. Here, we used a conditional knockout Hif-1α mouse model together with a standard chemotherapy regimen to evaluate LSC targeting in AML. Contrary to expectation, our studies revealed that Hif-1α-deleted-leukemias displayed a faster disease progression after chemotherapy. Our studies thereby challenge the general notion of cancer stem cell sensitization by inhibition of the HIF pathway, and warrant caution when applying HIF inhibition in combination with chemotherapy in AML. : In this article, Bryder, Velasco-Hernandez and colleagues show that the combination of chemotherapy and Hif-1α deletion in a murine model of MLL-AF9-AML leads to a faster progression of the disease without altering LSCs frequency. Single-cell transcriptional analysis indicates that Hif-1α deletion leads to few transcriptional modifications. Keywords: hypoxia, HIF-1α, acute myeloid leukemia, single-cell transcriptional analysis, chemotherapy, mouse mode