INTEGRATION PATTERNS OF HTLV-I PROVIRUS IN RELATION TO THE CLINICAL COURSE OF ATL - FREQUENT CLONAL CHANGE AT CRISIS FROM INDOLENT DISEASE

We examined human T-lymphotropic virus type I (HTLV-I) DNA integration in 68 patients with adult T-cell leukemia/lymphoma (ATL) by Southern blotting using EcoRI, which does not cut within the 9 kb of the genome and probes for pX and gag-pol region of HTLV-I. We detected defective proviral integration as a monoclonal band of various sizes with the p X but not with the gag-pol probe, or a monoclonal band of less than 9 kb with the pX probe, in 20 patients (29.4%). These were designated de fective (D) type. With both probes, a single band greater than 9 kb wa s detected in 34 (50.0%), designated complete (C) type, and two or mor e bands greater than 9 kb, were designated multiple (M) type, in 14 (2 0.6%). Advanced age, a high LDH value, and hypercalcemia were more fre quent in D type patients. The median survival time (MST) was 6.8, 24.4 , and 33.3 months, for D, C, and M types, respectively (log rank P = . 006). Among 52 sequentially examined patients, the HTLV-I integration patterns changed in 4 (7.5%). In three of these four, the rearrangemen ts of the T-cell receptor (TCR)b gene concomitantly changed, suggestin g the appearance of a new ATL clone. Another patient had the same rear rangement of the TCRb gene, indicating clonal evolution. The HTLV-I in tegration pattern changed at crisis from indolent to aggressive ATL in three patients. These findings suggested that the HTLV-I integration patterns have clinical implications in ATL pathophysiology. In contras t to the clonal evolution characteristic of the multistep carcinogenes is of most human malignancies, the frequent clonal change of ATL at cr isis is a peculiar phenomenon, probably reflecting the emergence of mu ltiple premalignant clones in viral leukemogenesis as suggested in Eps tein-Barr virus associated lymphomagenesis in the immunocompromised ho st. (C) 1997 by The American Society of Hematology.