Krüppel-like Factor 4 Supports the Expansion of Leukemia Stem Cells in MLL-AF9-driven Acute Myeloid Leukemia.

Autor:	Lewis AH; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA., Bridges CS; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA., Moorshead DN; Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, TX, USA., Chen TJ; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA., Du W; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA., Zorman B; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA., Sumazin P, Puppi M; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA., Lacorazza HD; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
Jazyk:	angličtina
Zdroj:	Stem cells (Dayton, Ohio) [Stem Cells] 2022 Aug 25; Vol. 40 (8), pp. 736-750.
DOI:	10.1093/stmcls/sxac033
Abstrakt:	Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow with 5-year overall survival of less than 10% in patients over the age of 65. Limited progress has been made in the patient outcome because of the inability to selectively eradicate the leukemic stem cells (LSC) driving the refractory and relapsed disease. Herein, we investigated the role of the reprogramming factor KLF4 in AML because of its critical role in the self-renewal and stemness of embryonic and cancer stem cells. Using a conditional Cre-lox Klf4 deletion system and the MLL-AF9 retroviral mouse model, we demonstrated that loss-of-KLF4 does not significantly affect the induction of leukemia but markedly decreased the frequency of LSCs evaluated in limiting-dose transplantation studies. Loss of KLF4 in leukemic granulocyte-macrophage progenitors (L-GMP), a population enriched for AML LSCs, showed lessened clonogenicity and percentage in the G2/M phase of the cell cycle. RNAseq analysis of purified L-GMPs revealed decreased expression of stemness genes and MLL-target genes and upregulation of the RNA sensing helicase DDX58. However, silencing of DDX58 in KLF4 knockout leukemia indicated that DDX58 is not mediating this phenotype. CRISPR/Cas9 deletion of KLF4 in MOLM13 cell line and AML patient-derived xenograft cells showed impaired expansion in vitro and in vivo associated with a defective G2/M checkpoint. Collectively, our data suggest a mechanism in which KLF4 promotes leukemia progression by establishing a gene expression profile in AML LSCs supporting cell division and stemness. (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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