Analysis of TCR, pTα, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment

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 pTalpha transcription in 114 T-ALLs demonstrated that they largely reflect physiologic T-lymphoid development. Half the TCRalphabeta lineage T-ALLs expressed a pre-TCR, as evidenced by RAG-1, pTalpha, and cTCRbeta expression, absence of TCRdelta deletion, and a sCD3(-), CD1a(+),CD4/8 double-positive(DP)phenotype, in keeping with a population undergoing beta selection. Most TCRgammadelta T-ALLs were pTalpha, terminal deoxynucleotidyl transferase (TdT), and RAG-1(lo/neg), double-negative/single-positive (DN/SP), and demonstrated only TCRbeta DJ rearrangement, whereas 40% were pTalpha, TdT, and RAG-1 positive, DIP, and demonstrated TCRbeta V(D)J rearrangement, with cTCRbeta expression in proportion. As such they may correspond to TCRalphabeta lineage precursors selected by TCRgammadelta expression, to early gammadelta cells recently derived from a pTalpha(+) common alphabeta/gammadelta precursor, or to a lineage-deregulated alphabeta/gammadelta intermediate. Approximately 30% of T-ALLs were sCD3/ cTCRbeta(-) 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, pTalpha, and RAG-1 low/negative, despite immature TCRdelta and TCRgamma 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.