急性淋巴细胞白血病病人Ikaros6基因表达及意义

EXPRESSION OF IKAROS6 ISOFORMS AND ITS SIGNIFICANCE IN PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

目的探讨Ikaros6基因在急性淋巴细胞白血病（ALL）病人中的表达及临床意义。方法对95例ALL病人进行R-显带染色体核型分析,再采用逆转录PCR方法检测Ikaros6基因的表达,基因测序确定Ikaros6基因突变的位置及类型;应用荧光定量PCR测定初诊及缓解病人Ikaros6mRNA的表达,并通过临床随访观察不同病人采用不同治疗方案的疗效。结果 95例ALL病人中有45例Ph染色体阳性,50例Ph染色体阴性;在Ph染色体阳性和阴性病人中分别有13例和2例表达Ikaros6,差异有显著性（χ2=11.03,P〈0.05）。健康对照组均未检测到Ikaros6基因的表达。表达Ikaros6的病人基因测序均显示IKZF1中外显子4~7的缺失。初诊病人Ikaros6mRNA平均表达量明显高于缓解病人（t=4.054,P〈0.05）。Ph染色体阳性ALL病人接受络氨酸酶抑制剂（TKIs）治疗后,有Ikaros6基因表达的病人其缓解率明显低于未表达该基因病人（χ2=6.20,P〈0.05）;未表达Ikaros6基因Ph染色体阳性ALL病人,接受TKIs治疗的缓解率明显高于VDCP治疗方案（χ2=5.43,P〈0.05）。表达Ikaros6的Ph染色体阳性ALL病人20个月平均累积复发时间明显短于未表达Ikaros6病人（Waldχ2=13.72,P〈0.05）。结论 IKZF1外显子4~7缺失导致Ikaros6基因在Ph染色体阳性ALL病人中高表达,表达该基因的病人对TKIs具有明显的抵抗作用,TKIs和VDCP方案对于此类病人的治疗效果均不理想,复发率高。

Objective To explore the expression of Ikaros6 in patients with acute lymphoblastic leukemia （ALL） and its clinical significance. Methods R handing chromosome karyotyping was performed in 95 cases of ALL, reverse transcription PCR （RT-PCR） was then applied to detect the expression of Ikaros6, employing gene sequencing to determine the location and type of mutation of Ikaros6. The expressions of Ikaros6 mRNA in primarily diagnosed and remission patients were detected using fluo rescent quantitation PCR. The efficacy in patients received different therapies were investigated through clinical follow up. Results Of 95 ALL patients, 45 showed positive Ph chromosome and 50 negative, there were 13 with Ikaros6 expression in that with positive Ph chromosome and two in that with negative Ph chromosome, the difference being significant （x2 = 11.03, P〈O.05）. No Ikaros6 expressions were detected in healthy controls. The gene sequencing indicated absence of exons 4-7 in IKZF1 gene in patients with positive Ikaros6 expression. The average expression of Ikaros6 mRNA in the primarily diagnosed patients was ohvi ously higher than the remission ones （t = 4.054, P〈0.05）. After TKIs therapy, the remission rate in patients with positive Ikaros6 was obviously lower than those with negative Ikaros6 （x2 =6.20,P〈0.05）. In the patients with positive Ph chromosome without Ikaros6, the remission rate after TKIs therapy was higher than VDCP therapy （x2 =5.43,P〈0.05）. In the patients with positive Ph chromosome who expressed Ikaros6, the 20-month average accumulation recurrence time was shorter than those without expression of Ikaros6 （Wald x2=13.72,P〈0.05）. Conclusion The deletion of IKZF1 exons 4-7 results in high expression of lkaros6 in Ph chromosome-positive patients with acute lymphoblastic leukemia, the patients with that expression show a dramatic resistance to TKIs. Both TKIs and VDCP protocols are not ideal in the therapy of this kind of patients because of a high recurrence rate.