Loss-of-function but not dominant-negative intragenic deletions are associated with an adverse prognosis in adult -negative acute lymphoblastic leukemia.

Genetic alterations of the transcription factor IKZF1 ("IKAROS") are detected in around 15-30% of cases of -negative B-cell precursor acute lymphoblastic leukemia. Different types of intragenic deletions have been observed, resulting in a functionally inactivated allele ("loss-of-function") or in "dominant-negative" isoforms. The prognostic impact of these alterations especially in adult acute lymphoblastic leukemia is not well defined. We analyzed 482 well-characterized cases of adult -negative B-precursor acute lymphoblastic leukemia uniformly treated in the framework of the GMALL studies and detected alterations in 128 cases (27%). In 20%, the alteration was present in a large fraction of leukemic cells ("high deletion load") while in 7% it was detected only in small subclones ("low deletion load"). Some patients showed more than one alteration (8%). Patients exhibiting a loss-of-function isoform with high deletion load had a shorter overall survival (OS at 5 years 28% 59%; <0.0001), also significant in a subgroup analysis of standard risk patients according to GMALL classification (OS at 5 years 37% 68%; =0.0002). Low deletion load or dominant-negative alterations had no prognostic impact. The results thus suggest that there is a clear distinction between loss-of-function and dominant-negative deletions. Affected patients should thus be monitored for minimal residual disease carefully to detect incipient relapses at an early stage and they are potential candidates for alternative or intensified treatment regimes. ().