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

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
Organisations
External organisations
  • Linköping University Hospital
  • Linköping University
  • University of Gothenburg
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Cancer and Oncology

Keywords

  • acute myeloid leukemia, chemotherapy, HIF-1α, hypoxia, mouse model, single-cell transcriptional analysis
Original languageEnglish
Pages (from-to)112-121
Number of pages10
JournalStem Cell Reports
Volume12
Issue number1
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes