Page 157 - Haematologica April 2020

Acute Myeloid Leukemia
Clinical and preclinical characterization of CD99 isoforms in acute myeloid leukemia
Vijaya Pooja Vaikari,1 Yang Du,1 Sharon Wu,1 Tian Zhang,2 Klaus Metzeler,3 Aarif M.N. Batcha,4,5 Tobias Herold,3,6 Wolfgang Hiddemann,3 Mojtaba Akhtari7 and Houda Alachkar1,7
1Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA; 2Medical Biology Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 3Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany; 4Institute of Medical Data Processing, Biometrics and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Munich, Germany; 5Data Integration for Future Medicine (DiFuture, www.difuture.de), LMU Munich, Germany; 6Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), Munich Germany and 7USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles Southern California, Los Angeles, CA, USA
ABSTRACT
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 trans- membrane protein expressed on leukocytes and plays a role in cell adhe- sion, 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 mod- els, the CD99 long isoform delayed disease progression and resulted in lower leukemia engraftment 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 preclin- ical development of CD99 targeted therapy.
Introduction
The outcome of patients with acute myeloid leukemia (AML) remains dismal due to the high relapse rate.1 To identify target genes that were differentially over- expressed in AML compared with normal hematopoietic cells, we leveraged genomic and transcriptomic data and discovered CD99.
CD99, a membrane glycoprotein,2 is normally expressed in cortical thymocytes, mature plasma cells, granulosa cells of the ovary, Sertoli cells of the testis, and pan- creatic islet cells.3 The CD99 gene encodes two distinct proteins that are produced by alternative splicing of the CD99 transcript. The alternative spliced short isoform results from a deletion in its intracytoplasmic fragment.2 CD99 plays a role in cell migration,4 adhesion, differentiation of thymocytes and T cells,2 and regulation of diapedesis.5 In cancer cells, CD99 is highly expressed on the cell surface of Ewing's sarcoma (EWS),6 gliomas7 and other mesenchymal,8,9 hematopoietic,10-12 and epithe- lial cancers.13,14 In EWS, engagement with the anti-CD99 antibody enhanced apop- tosis and sensitivity to chemotherapy.15 High CD99 correlated with enhanced inva- sion of glioma cells.7
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):999-1012
Correspondence:
HOUDA ALACHKAR
alachkar@usc.edu
Received: September 17, 2018. Accepted: July 25, 2019. Pre-published: August 1, 2019..
doi:10.3324/haematol.2018.207001
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/999
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