Expression of Ikaros Isoform 6 in Chinese Children With Acute Lymphoblastic Leukemia

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Abstract
Ikaros is a zinc-finger transcription factor that plays an important role in the differentiation and proliferation of lymphocytes. Dominant-negative Ikaros isoform 6 (Ik6), one of its common subtypes, is overexpressed in leukemia patients and is associated with unfavorable prognosis in childhood B-cell progenitor acute lymphoblastic leukemia (ALL). This study was to identify specific isoforms, especially Ik6, in Chinese pediatric patients with ALL. The mRNA expression of Ikaros was detected in 88 children with previously untreated ALL by nested reverse transcription-polymerase chain reaction (RT-PCR). Sequencing of the PCR products was performed to identify specific isoforms. The expression of fusion genes was determined by using multiplex RT-PCR. The functional isoforms Ik1, Ik2/3, and dominant negative isoforms Ik4, 6, 8, 9, 10 identified by nested RT-PCR were further confirmed by sequence analysis. In the 88 cases, the Ik6 was found to be overexpressed in 8 of 70 cases of B-lineage ALL and in 1 of 18 cases of T-lineage ALL patients. Among Ik6 B-lineage ALL patients, 3 had expression of BCR/ABL fusion gene and 1 had HOX11 expression. Ik6 overexpression was independent of age, white blood cell count at diagnosis, risk group, and expression of the fusion genes currently measured in China except BCR/ABL (P<0.01). And it was strongly associated with elevated levels of minimal residual disease at day 28 (P<0.01). Ik6 can be included as a high-risk factor at diagnosis. In developing countries with limited resources, it can be economically detected by nested RT-PCR.

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