The Coexpression of AML1-ETO9a Isoform and AML1-ETO in Acute Myeloid Leukemia M2 Subtype and Its Clinical Significance.

Abstract

Previous studies on either animal model or clinical settings have demonstrated that the expression of AML1/ETO9a (AE9a), a truncated version of AML1-ETO (AE) generated by alternative splicing during transcription, in patients with acute myeloid leukemia M2 subtype may have clinical significance. Moreover, the simultaneously expression of both AE and AE9a may even be more meaningful to the prognosis of the patients. To validate this hypothesis, we have measured the mRNA level of both AE and AE9a in each individual M2 patient by quantitative real-time RT-PCR, and correlated the ratio of AE/AE9a mRNA levels with the clinical outcome and prognosis in these patients. In 35 newly-diagnosed AML-M2 patients with t(8;21), expression of AE9a was detected in 30 cases (85.71%). The median value of the percentages of AE9a and AE within overall transcripts of the fusion gene in these patients were 18.16% and 81.84%, respectively (p<0.05). A positive correlation between the mRNA level of AE9a and AE was shown in 45 bone marrow samples from 19 patients during the follow-up, and the correlation coefficient was 0.900(P<0.01). The expression level of both AE9a and AE decreased in 16 patients after one course of standard conventional chemotherapy. Among them, a reduced percentage of AE9a mRNA level was prominent in 11 (68.75%) patients, while the percentage of mRNA level of AE decreased in 5 (31.25%) cases. The complete remission rate after first course of chemotherapy was 81.82%(9/11)in 11 patients, and 20.00%(1/5)in 5 patients, suggesting a higher CR rate in those patients who exhibited more conspicuous decrease in mRNA level of AE9a (P<0.05). The percentage of AE9a mRNA in the total fusion transcripts rose in all of the 5 relapsing cases. In a retrospective study on 92 patients of AML-M2 including 50 cases with t(8;21) and 42 case with either normal karyotype or other chromosome abnormalities, expression of AE9a has been found in these 50 cases by conventional RT-PCR. Between the AE9a positive and negative groups, no statistically significant difference had been found in complete remission rate, relapsing rate and the first CR period over a follow-up with medium time of 13 months (4–76 mths). However, 22 months of medium survival in AE9a positive group (38 cases) was remarkably shorter than 70 months in AE9a negative group (25 cases). Our results indicated that the mRNA of AE9a at a relatively lower level co-expressed with AE in most AML-M2 patients with t(8;21) translocation. The expression level of AE9a rather than AE may play more crucial role in development and progress of leukemia. AE9a positive patients have distinctly shorter survival time than the negative cases, predicting a worse prognosis.