MOLECULAR-REARRANGEMENTS OF THE MLL GENE ARE PRESENT IN MOST CASES OFINFANT ACUTE MYELOID-LEUKEMIA AND ARE STRONGLY CORRELATED WITH MONOCYTIC OR MYELOMONOCYTIC PHENOTYPES

Cytogenetic studies have previously identified abnormalities of chromo some band 11q23 in many cases of infant acute leukemia. Recent studies by ourselves and others have demonstrated breakpoint clustering in ac ute leukemias bearing translocations involving 11q23, and a Drosophila trithorax gene homologue (called MLL, HRX, or ALL-I) has been shown t o span the 11q23 breakpoints of these translocations. To determine if this gene is affected in infant acute myeloid leukemia (AML), we have analyzed 26 infant AML cases for molecular alterations of this 11q23 g ene. 15 out of 26 cases studied (58%) showed rearrangement of the MLL gene at the molecular level, and these rearrangements were clustered w ithin an similar to 11-kb region containing nine exons of this gene. M oreover, 14 of the 15 cases with 11q23 rearrangements (93%) had myelom onocytic or monocytic phenotypes (M4 or M5 FAB subtypes, respectively) , both of which are associated with a poor prognosis in childhood AML. In contrast, only 1 of 11 nonrearranged cases had an M4 or M5 phenoty pe (P = 0.00002). Rearrangement also correlated significantly with hyp erleukocytosis (P = 0.02), another clinical parameter associated with poor outcome in this disease. Our results demonstrate that molecular r earrangements of MLL are common in M4 or M5 infant ARIL, and suggest t hat alteration of this gene may result in abnormal control of prolifer ation and differentiation in monocytic progenitor cells.