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

Autor: Shamit Soneji, David Bryder, Talia Velasco-Hernandez, Eva Erlandsson, Isabel Hidalgo, Jörg Cammenga
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
medicine.medical_specialty
Oncogene Proteins
Fusion
medicine.medical_treatment
mouse model
HIF-1α
Antineoplastic Agents
Biology
acute myeloid leukemia
chemotherapy
Biochemistry
Article
03 medical and health sciences
Mice
0302 clinical medicine
Cancer stem cell
Internal medicine
hemic and lymphatic diseases
Conditional gene knockout
Genetics
medicine
Animals
Protein Interaction Maps
lcsh:QH301-705.5
Sensitization
Myeloid Progenitor Cells
Chemotherapy
lcsh:R5-920
Hematology
hypoxia
single-cell transcriptional analysis
Myeloid leukemia
Cell Biology
Chemotherapy regimen
3. Good health
Leukemia
Myeloid
Acute
030104 developmental biology
medicine.anatomical_structure
lcsh:Biology (General)
Cancer research
Hypoxia-Inducible Factor 1
Stem cell
Single-Cell Analysis
lcsh:Medicine (General)
030217 neurology & neurosurgery
Gene Deletion
Developmental Biology
Zdroj: Stem Cell Reports, Vol 12, Iss 1, Pp 112-121 (2019)
Stem Cell Reports
ISSN: 2213-6711
Popis: 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.
Graphical Abstract
Highlights • Deletion of Hif-1α accelerates the progression of chemotherapy-treated MLL-AF9-AML • Deletion of Hif-1α does not decrease LSC frequency after chemotherapy • Chemotherapy targets more mature cells indicated by transcriptional analysis • Hif-1α deletion affects few transcriptional pathways in AML cells
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.
Databáze: OpenAIRE
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