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Clinical and preclinical characterization of CD99 isoforms in acute myeloid leukemia.
Haematologica 105, 999-1012 (2020)
In an effort to identify target genes in acute myeloid leukemia (AML), we compared gene expression profiles between normal and AML cells from various publicly available datasets. We identified CD99, a gene that is up-regulated in AML patients. In 186 patients from The Cancer Genome Atlas AML dataset, CD99 was over-expressed in patients with FLT3-ITD and was down-regulated in patients with TP53 mutations. CD99 is a transmembrane protein expressed on leukocytes and plays a role in cell adhesion, trans-endothelial migration, and T-cell differentiation. The CD99 gene encodes two isoforms with distinct expression and functional profiles in both normal and malignant tissues. Here we report that, although the CD99 long isoform initially induces an increase in cell proliferation, it also induces higher levels of reactive oxygen species, DNA damage, apoptosis and a subsequent decrease in cell viability. In several leukemia murine models, the CD99 long isoform delayed disease progression and resulted in lower leukemia engrafurient in the bone marrow. Furthermore, the CD99 monoclonal antibody reduced cell viability, colony formation, and cell migration, and induced cell differentiation and apoptosis in leukemia cell lines and primary blasts. Mechanistically, CD99 long isoform resulted in transient induction followed by a dramatic decrease in both ERK and SRC phosphorylation. Altogether, our study provides new insights into the role of CD99 isoforms in AML that could potentially be relevant for the preclinical development of CD99 targeted therapy.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Acute Myeloid Leukemia ; Cd99 ; Flt3-itd ; Hematopoietic Stem Cell ; Therapeutic Target; Mic2 Expression; Ewings-sarcoma; Frequent Expression; Splice Variant; Cell Adhesion; Immunoreactivity; Kinase; Activation; Hodgkins; Lymphoma
ISSN (print) / ISBN
0390-6078
e-ISSN
1592-8721
Quellenangaben
Volume: 105,
Issue: 4,
Pages: 999-1012
Publisher
Ferrata Storti Foundation
Publishing Place
Via Giuseppe Belli 4, 27100 Pavia, Italy
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)