Ikaros, a zinc finger-containing
DNA-binding protein, is required for normal lymphocyte development, and germline mutant mice that express only non-
DNA binding dominant-negative "leukemogenic" Ikaros
isoforms lacking critical N-terminal zinc fingers develop an aggressive form of
lymphoblastic leukemia 3-6 months after birth. Therefore, we sought to determine whether molecular abnormalities involving the Ikaros gene could contribute to the development of
acute lymphoblastic leukemia (ALL) in infants. Primary leukemic cells were freshly obtained from 12 infants (<1 year of age) with newly diagnosed ALL. In leukemic cells from each of the 12 infants with ALL, we found high level expression of dominant-negative
isoforms of Ikaros with abnormal subcellular compartmentalization patterns. PCR cloning and
nucleotide sequencing were used to identify the specific Ikaros
isoforms and detect Ikaros gene mutations in these cells. Leukemic cells from seven of seven infants with ALL, including five of five MLL-AF4(+) infants, expressed dominant-negative Ikaros
isoforms Ik-4, Ik-7, and Ik-8 that lack critical N-terminal zinc fingers. In six of seven patients, we detected a specific mutation leading to an in-frame deletion of 10
amino acids (Delta KSSMPQKFLG) upstream of the transcription activation domain adjacent to the C-terminal zinc fingers of Ik-2, Ik-4, Ik-7, and Ik-8. In contrast, only wild-type Ik-1 and Ik-2
isoforms with normal nuclear localization were found in normal infant bone marrow cells and infant thymocytes. These results implicate the expression of dominant-negative Ikaros
isoforms and the disruption of normal Ikaros function in the leukemogenesis of ALL in infants.