The Expression Pattern of Different Ikaros Isoforms In Adult B-Cell Acute Lymphoblastic Leukemia

Abstract 4325

Ikaros plays an important role in the control of differentiation and proliferation of all lymphoid lineages. The multiple isoforms that lack different numbers of exons have different functions. The most previous studies focused on acute lymphoblastic leukemia(ALL) patients with Philadelphia chromosome. To investigate the expression pattern of different Ikaros isoforms in both BCR-ABL positive and BCR-ABL negative ALL, especially those in a normal karyotype. 114 adult B-ALL patients at diagnosis were involved in this study. 20 healthy normal volunteers and patients with leukemia in remission were also analyzed for Ikaros expression. The expression of different wild-type and aberrant Ikaros transcripts were detected and quantified by a fast, high-throughput capillary electrophoresis sizing method. The relative expression level of one isoform in a sample was calculated as the expression level of this isoform divided by the sum of expression level of all kinds of isoform in this sample. In 62 cases of BCR-ABL positive ALL, 32 patients(52%) expressed only non-DNA-binding isoforms, which consisted of Ik6(28/32,88%), Ik6+Ik6 ¢(3/32, 9%) and Ik6 ¢(1/32, 3%). 30 patients (49%) simultaneously expressed multiple Ikaros variants in a single sample corresponding to the wild-type Ik6 ¢ AIk6 AIk8 AIk4A AIk4 AIk5A AIk2 and aberrant Ik2(ins) AIk2(ins+del) AIk4(ins) and Ik4 (ins+del). The median value of relative expression level of each isoform was 0.01 A0.19 A0.07 A0.06 A0.22 A0.06 A0.23 A0.35 A0.11 A0.17 and 0.11, respectively. In 52 cases of BCR-ABL negative ALL, including 27 cases with a normal karyotype and 25 cases with recurring chromosomal abnormality other than t(9;22), 7 patients(13%) expressed only non-DNA-binding isoforms, which consisted of Ik6(2/7,29%) and Ik6+Ik6 ¢(5/7,71%). Notably, all of 7 patients have a normal karyotype. Therefore, the frequency of expression of only non-DNA-binding isoforms in patients with a normal karyotype was 39%(7/27), Whereas coexpression of multiple variants were identified in 45 patients (85%). The median value of relative expression level of each isoform was 0.01 A0.15 A0.11 A0.07 A0.25 A0.09 A0.25 A0.3 A0.16 A0.18 and 0.14 for Ik6 ¢ AIk6 AIk8 AIk4A AIk4 AIk5A AIk2 AIk2(ins) AIk2(ins+del) AIk4(ins) and Ik4 (ins+del), respectively. There was no statistical difference in relative expression level of different Ikaros variants between groups, except for Ik6. In normal donors, the median value of relative expression level of each isoform was 0 A0.09 A0.07 A0.06 A0.24 A0.12 A0.35 A0.49 A0.13 A0.18 and 0.07 for Ik6 ¢ AIk6 AIk8 AIk4A AIk4 AIk5A and Ik2 AIk2(ins) AIk2(ins+del) AIk4(ins) and Ik4 (ins+del),respectively. In comparison with normal donors, the expression of Ik2 AIk5A and Ik2(ins) are relatively lower, while the expression of Ik6 and Ik4(ins+del) are relatively higher in adult ALL patients. These results indicated that disproportional expression of different Ikaros isoforms could contribute to leukemogenesis. The overexpression of non-DNA- binding isoform, largely coexpression of Ik6 and Ik6 ¢, usually existed in patients with a normal karyotype, These information could help in the further classification of adult ALL subgroup and individualized treatment.