FREQUENT ONGOING T-CELL RECEPTOR REARRANGEMENTS IN CHILDHOOD B-PRECURSOR ACUTE LYMPHOBLASTIC-LEUKEMIA - IMPLICATIONS FOR MONITORING MINIMALRESIDUAL DISEASE

Crosslineage T-cell receptor delta (TCR delta) rearrangements are wide ly used as tumor markers for the follow up of minimal residual disease in childhood B-precursor acute lymphoblastic leukemia (ALL) by polyme rase chain reaction (PCR). The major drawback of this approach is the risk of false-negative results due to clonal evolution. We investigate d the stability of V delta 2D delta 3 rearrangements in a group of 56 childhood B-precursor ALL patients by PCR and Southern blot analysis. At the PCR level, V delta 2D delta 3-to-J alpha rearranged subclones ( one pathway for secondary TCR delta recombination) were demonstrated i n 85.2% of V delta 2D delta 3-positive patients tested, which showed t hat small subclones are present in the large majority of patients desp ite apparently monoclonal TCR delta Southern blot patterns. Sequence a nalysis of V delta 2D delta 3J alpha rearrangements showed a biased J alpha gene usage, with HAPO5 and J alpha F in 26 of 32 and 6 of 32 clo nes, respectively. Comparison of V delta 2D delta 3 rearrangement stat us between diagnosis and first relapse showed differences in seven of eight patients studied. In contrast, from first relapse onward. no clo nal changes were observed in six patients studied. To investigate the occurrence of crosslineage TCR delta rearrangements in normal B and T cells, fluorescence-activated cell sorter-sorted peripheral blood CD10 (+)/CD3(-) and CD19(-)/CD3(+) cell populations from three healthy dono rs were analyzed. V delta 2D delta 3 rearrangements were detected at l ow frequencies in both B and T cells, which suggests that V delta 2-to -D delta 3 joining also occurs during normal B-cell differentiation. A model for crosslineage Tops rearrangements in B-precursor ALL is dedu ced that explains the observed clonal changes between diagnosis and re lapse and is compatible with multistep leukemogenesis of B-precursor A LL. (C) 1995 by The American Society of Hematology.