Investigating CD99 Expression in Leukemia Propagating Cells in Childhood T Cell Acute Lymphoblastic Leukemia

• Published in: PloS one Vol. 11; no. 10; p. e0165210
• Main Authors: Cox, Charlotte V, Diamanti, Paraskevi, Moppett, John P, Blair, Allison
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.10.2016; Public Library of Science (PLoS)
• Subjects: 12E7 Antigen - metabolism; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adolescent; Animals; Antigens; Antigens, CD34 - metabolism; Biology and Life Sciences; Blast cells; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; CD34 antigen; CD99 antigen; Cell Proliferation; Cell self-renewal; Cells, Cultured; Child; Child, Preschool; Children; Cloning; Comparative analysis; Early experience; Female; Flow Cytometry; Gene expression; Genomes; Health aspects; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; In Situ Hybridization, Fluorescence; Karyotype; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Male; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred NOD; Patients; Pediatrics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - diagnosis; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Research and Analysis Methods; Stem cell transplantation; Stem cells; Subpopulations; T cell receptors; T cells; T-cell receptor; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Therapeutic applications; Transplants; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165210

A significant number of children with T-lineage acute lymphoblastic leukemia (T-ALL) fail to respond to therapy and experience early relapse. CD99 has been shown to be overexpressed on T-ALL cells and is considered to be a reliable detector of the disease. However, the relevance of CD99 overexpression in ALL has not been investigated in a functional context. The aim of this study was to investigate the functional capacity of CD99+ cells in childhood ALL and determine the suitability of CD99 as a therapeutic target. Flow cytometric analyses confirmed higher expression of CD99 in ALL blasts (81.5±22.7%) compared to normal hemopoietic stem cells (27.5±21.9%) and T cells (3.1±5.2%, P≤0.004). When ALL cells were sorted and assessed in functional assays, all 4 subpopulations (CD34+/CD99+, CD34+/CD99-, CD34-/CD99+ and CD34-/CD99-) could proliferate in vitro and establish leukemia in NSG mice. Leukemia propagating cell frequencies ranged from 1 in 300 to 1 in 7.4x104 but were highest in the CD34+/CD99- subpopulation. In addition, all four subpopulations had self-renewal ability in secondary NSG mice. Cells in each subpopulation contained patient specific TCR rearrangements and karyotypic changes that were preserved with passage through serial NSG transplants. Despite high levels of CD99 antigen on the majority of blast cells, leukemia initiating capacity in vivo was not restricted to cells that express this protein. Consequently, targeting CD99 alone would not eliminate all T-ALL cells with the ability to maintain the disease. The challenge remains to develop therapeutic strategies that can eliminate all leukemia cells with self-renewal capacity in vivo.