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

Velasco-Hernandez, Talia LU ; Soneji, Shamit LU ; Hidalgo, Isabel LU orcid ; Erlandsson, Eva LU ; Cammenga, Jörg LU and Bryder, David LU (2019) In Stem Cell Reports 12(1). p.112-121
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... (More)

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.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
acute myeloid leukemia, chemotherapy, HIF-1α, hypoxia, mouse model, single-cell transcriptional analysis
in
Stem Cell Reports
volume
12
issue
1
pages
10 pages
publisher
Cell Press
external identifiers
  • scopus:85059581160
  • pmid:30595549
ISSN
2213-6711
DOI
10.1016/j.stemcr.2018.11.023
language
English
LU publication?
yes
id
2a443750-5c47-46aa-b741-ee0218c21f8b
date added to LUP
2019-01-17 14:55:33
date last changed
2024-04-15 22:14:58
@article{2a443750-5c47-46aa-b741-ee0218c21f8b,
  abstract     = {{<p>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.</p>}},
  author       = {{Velasco-Hernandez, Talia and Soneji, Shamit and Hidalgo, Isabel and Erlandsson, Eva and Cammenga, Jörg and Bryder, David}},
  issn         = {{2213-6711}},
  keywords     = {{acute myeloid leukemia; chemotherapy; HIF-1α; hypoxia; mouse model; single-cell transcriptional analysis}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{112--121}},
  publisher    = {{Cell Press}},
  series       = {{Stem Cell Reports}},
  title        = {{Hif-1α Deletion May Lead to Adverse Treatment Effect in a Mouse Model of MLL-AF9-Driven AML}},
  url          = {{http://dx.doi.org/10.1016/j.stemcr.2018.11.023}},
  doi          = {{10.1016/j.stemcr.2018.11.023}},
  volume       = {{12}},
  year         = {{2019}},
}