Loss-of-function but not dominant-negative intragenic IKZF1 deletions are
associated with an adverse prognosis in adult BCR-ABL-negative acute
lymphoblastic leukemia
Genetic alterations of the transcription factor IKZF1 (“IKAROS”) are detected
in around 15–30% of cases of BCR-ABL-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 BCR-ABL-negative B-precursor
acute lymphoblastic leukemia uniformly treated in the framework of the GMALL
studies and detected IKZF1 alterations in 128 cases (27%). In 20%, the IKZF1
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 IKZF1 alteration (8%). Patients
exhibiting a loss-of-function isoform with high deletion load had a shorter
overall survival (OS at 5 years 28% vs. 59%; P<0.0001), also significant in a
subgroup analysis of standard risk patients according to GMALL classification
(OS at 5 years 37% vs. 68%; P=0.0002). Low deletion load or dominant-negative
IKZF1 alterations had no prognostic impact. The results thus suggest that
there is a clear distinction between loss-of-function and dominant-negative
IKZF1 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. (clinicaltrials.gov identifiers: 00199056 and 00198991)