TEL-AML1 fusion precedes differentiation to pre-B cells in childhood acute lymphoblastic leukemia.
The TEL-AML1 gene fusion results from a karyotypically cryptic t(12;21) translocation, the most common genetic abnormality in pediatric acute lymphoblastic leukemia (ALL). The presence of the TEL-AML1 fusion in utero, its protracted latency to overt leukemia, and secondary loss of the untranslocated TEL suggest it is an initiating event. Sequences of the TEL-AML1 genomic breakpoint and the immunoglobulin heavy chain (IgH) and/or T-cell receptor (TCR) gene rearrangements were characterized in four pediatric pre-B ALL patients. Analysis of these markers in relapsed patients revealed that immunophenotypically and cytogenetically distinct, and clonally unrelated antigen receptor leukemic cell populations harbored the same initiating TEL-AML1 molecular abnormality. Furthermore, TEL-AML1-positive cells persisted during remission even in the absence of detectable clone-specific IgH and TCR markers. We demonstrate that the TEL-AML1 translocation can occur in vivo during B-cell development before rearrangement of the IgH and TCR genes. We propose, in some cases, that the TEL-AML1 translocation occurs in a stem or B progenitor cell, and that recurrent TEL-AML1-positive pre-B ALL represents a de novo-transformed population that retains the same diagnostic initiating event.
Pine
Sharon R
SR
Children's Cancer Research Laboratory, Department of Pediatric, Hematology-Oncology, New York Medical College, Basic Science Building, Room 401, Valhalla, NY 10595, USA. sharon_pine@nymc.edu
Wiemels
Joseph L
JL
Jayabose
S
S
Sandoval
Claudio
C
D000293:Adolescent; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001483:Base Sequence; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage / Q000235:genetics; D002910:Chronology as Topic; D002999:Clone Cells / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit; D005260:Female; D019672:Genes, T-Cell Receptor; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016130:Immunophenotyping; D008297:Male; D008969:Molecular Sequence Data; D018365:Neoplasm, Residual / Q000235:genetics / Q000276:immunology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D012008:Recurrence; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D007143:Immunoglobulin Heavy Chains; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein