ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape

Autor: Daniela Lico, Annamaria Aloisio, Heather M. Bond, Emanuela Chiarella, Stefania Scicchitano, Emanuela G Cosentino, Maria Mesuraca, Antonino Neri, Katia Todoerti, Nicola Amodio
Přispěvatelé: Faculteit Medische Wetenschappen/UMCG
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Oncogene Proteins
Fusion
CD34
Apoptosis
Transcriptome
chromosomal translocations
PATHWAY
hemic and lymphatic diseases
Gene expression
MOLECULAR SUBTYPES
Tumor Cells
Cultured
PROGRAM
cord blood-derived hematopoietic stem cells (CB-CD34+)
Biology (General)
Spectroscopy
Hematopoietic stem cell
General Medicine
Prognosis
Computer Science Applications
Cell biology
mixed lineage leukemia gene (MLL) AF9 (MLLT3 or LTG9)
DNA-Binding Proteins
Gene Expression Regulation
Neoplastic
Survival Rate
Leukemia
Myeloid
Acute
Haematopoiesis
Chemistry
medicine.anatomical_structure
ZFP521
DIFFERENTIATION
Nucleophosmin
Myeloid-Lymphoid Leukemia Protein
TRANSITION
human zinc finger protein 521 (hZNF521)
QH301-705.5
Transgene
Biology
MLL-AF9
Article
Catalysis
Inorganic Chemistry
acute myeloid leukemia (AML)
MII-AF9
Biomarkers
Tumor
medicine
Humans
Gene silencing
Physical and Theoretical Chemistry
Progenitor cell
Molecular Biology
QD1-999
neoplasms
Cell Proliferation
cord blood-derived hematopoietic stem cells (CB-CD34(+))
fusion gene MLL-AF9
Organic Chemistry
LINEAGE COMMITMENT
PROFILES
Hematopoietic Stem Cells
gene expression
Zdroj: International Journal of Molecular Sciences
Volume 22
Issue 19
International Journal of Molecular Sciences, Vol 22, Iss 10814, p 10814 (2021)
International Journal of Molecular Sciences, 22(19):10814. MDPI AG
ISSN: 1422-0067
Popis: Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones.
Databáze: OpenAIRE
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