Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors
Linda Zuurbier,
Alejandro Gutierrez,
Charles G. Mullighan,
Kirsten Canté-Barrett,
A. Olivier Gevaert,
Johan de Rooi,
Yunlei Li,
Willem K. Smits,
Jessica G.C.A.M. Buijs-Gladdines,
Edwin Sonneveld,
A. Thomas Look,
Martin Horstmann,
Rob Pieters,
Jules P.P. Meijerink
Affiliations
Linda Zuurbier
Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Alejandro Gutierrez
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Division of Hematology/Oncology, Children’s Hospital, Boston, MA, USA
Charles G. Mullighan
Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA
Kirsten Canté-Barrett
Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
A. Olivier Gevaert
Center for Cancer Systems Biology (CCSB) and Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA
Johan de Rooi
Department of Biostatistics, Erasmus MC Rotterdam, Rotterdam, the Netherlands;Department of Bioinformatics, Erasmus MC Rotterdam, Rotterdam, the Netherlands
Yunlei Li
Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Willem K. Smits
Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Jessica G.C.A.M. Buijs-Gladdines
Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Edwin Sonneveld
Dutch Childhood Oncology Group (DCOG), the Hague, the Netherlands
A. Thomas Look
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Division of Hematology/Oncology, Children’s Hospital, Boston, MA, USA
Martin Horstmann
German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia (COALL), Hamburg, Germany;Research Institute Children's Cancer Center Hamburg, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Rob Pieters
Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands;Dutch Childhood Oncology Group (DCOG), the Hague, the Netherlands
Jules P.P. Meijerink
Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands
Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients.
