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Garg, S.* ; Reyes-Palomares, A.* ; He, L.* ; Bergeron, A.* ; Lavallée, V.P.* ; Lemieux, S.* ; Gendron, P.* ; Rohde, C.* ; Xia, J.* ; Jagdhane, P.* ; Müller-Tidow, C.* ; Lipka, D.B.* ; Imren, S.* ; Humphries, R.K.* ; Waskow, C.* ; Vick, B. ; Jeremias, I. ; Richard-Carpentier, G.* ; Hébert, J.* ; Sauvageau, G.* ; Zaugg, J.* ; Barabé, F.* ; Pabst, C.*

Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML.

Blood 134, 263-276 (2019)
Publ. Version/Full Text Postprint DOI
Open Access Green
FLT3, DNMT3A, and NPM1 are the most frequently mutated genes in cytogenetically normal acute myeloid leukemia (AML), but little is known about how these mutations synergize upon cooccurrence. Here we show that triple-mutated AML is characterized by high leukemia stem cell (LSC) frequency, an aberrant leukemia-specific GPR56highCD34low immunophenotype, and synergistic upregulation of Hepatic Leukemia Factor (HLF). Cell sorting based on the LSC marker GPR56 allowed isolation of triple-mutated from DNMT3A/NPM1 double-mutated subclones. Moreover, in DNMT3A R882-mutated patients, CpG hypomethylation at the HLF transcription start site correlated with high HLF mRNA expression, which was itself associated with poor survival. Loss of HLF via CRISPR/Cas9 significantly reduced the CD34+GPR56+ LSC compartment of primary human triple-mutated AML cells in serial xenotransplantation assays. HLF knockout cells were more actively cycling when freshly harvested from mice, but rapidly exhausted when reintroduced in culture. RNA sequencing of primary human triple-mutated AML cells after shRNA-mediated HLF knockdown revealed the NOTCH target Hairy and Enhancer of Split 1 (HES1) and the cyclin-dependent kinase inhibitor CDKN1C/p57 as novel targets of HLF, potentially mediating these effects. Overall, our data establish HLF as a novel LSC regulator in this genetically defined high-risk AML subgroup.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Acute Myeloid-leukemia; Gene-mutations; Tandem Duplication; Identification; Transplantation; Quiescence; P57(kip2); Impact; Blood; Hes1
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 134, Issue: 3, Pages: 263-276 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)