title: Analysis of TCR, pT alpha, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment.
abstract: T-acute lymphoblastic leukemias (T-ALLs) derive from human T-lymphoid precursors arrested at various early stages of development. Correlation of phenotype and T-cell receptor (TCR) status with RAG-1 and pT alpha transcription in 114 T-ALLs demonstrated that they largely reflect physiologic T-lymphoid development. Half the TCR alpha beta lineage T-ALLs expressed a pre-TCR, as evidenced by RAG-1, pT alpha, and cTCR beta expression, absence of TCR delta deletion, and a sCD3(-), CD1a(+), CD4/8 double-positive (DP) phenotype, in keeping with a population undergoing beta selection. Most TCR gamma delta T-ALLs were pT alpha, terminal deoxynucleotidyl transferase (TdT), and RAG-1(lo/neg), double-negative/single-positive (DN/SP), and demonstrated only TCR beta DJ rearrangement, whereas 40% were pT alpha, TdT, and RAG-1 positive, DP, and demonstrated TCR beta V(D)J rearrangement, with cTCR beta expression in proportion. As such they may correspond to TCR alpha beta lineage precursors selected by TCR gamma delta expression, to early gamma delta cells recently derived from a pT alpha(+) common alpha beta/gamma delta precursor, or to a lineage-deregulated alpha beta/gamma delta intermediate. Approximately 30% of T-ALLs were sCD3/cTCR beta(-) and corresponded to nonrestricted thymic precursors because they expressed non-T-restricted markers such as CD34, CD13, CD33, and CD56 and were predominantly DN, CD1a, pT alpha, and RAG-1 low/negative, despite immature TCR delta and TCR gamma rearrangements. TCR gene configuration identified progressive T-lymphoid restriction. T-ALLs, therefore, provide homogeneous expansions of minor human lymphoid precursor populations that can aid in the understanding of healthy human T-cell development.
authors.affiliation: Department of Biological and Clinical Hematology, Centre Hospitalier-Universitaire/Assistance Publique-Hopitaux de Paris (CHU/AP-HP) Necker-Enfants Malades and Université Paris V, France.
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Kheira
authors.initials: K
authors.lastname: Beldjord
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Boulanger
authors.forename: Béatrice
authors.initials: B
authors.lastname: Comba
authors.forename: Patricia
authors.initials: P
authors.lastname: Le Tutour
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Estienne
authors.forename: Frédéric
authors.initials: F
authors.lastname: Davi
authors.forename: Judith
authors.initials: J
authors.lastname: Landman-Parker
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.forename: Agnès
authors.initials: A
authors.lastname: Buzyn
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.forename: Françoise
authors.initials: F
authors.lastname: Valensi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D019070:Cell Lineage; D002648:Child; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000145:classification / Q000276:immunology / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000145:classification*; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D015703:Antigens, CD; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; C090377:pre-T cell receptor alpha; C064658:RAG-1 protein