Takenokuchi Mariko, Kawano Seiji, Nakamachi Yuji, Sakota Yasuyuki, Syampurnawati Meilani, Saigo Katsuyasu, Tatsumi Eiji, Kumagai Shunichi
Faculty of Pharmacological Sciences, Himeji Dokkyo University, Himeji, Hyogo; Japan;
Hematol Rep. 2012 Nov 19;4(4):e22. doi: 10.4081/hr.2012.e22. Epub 2012 Oct 16.
Acute promyelocytic leukemia (APL) is characterized by the specific PML-RARα fusion gene resulting from translocation t(15;17) (q22;q12). Internal tandem duplication (ITD) of the FLT3 gene has been observed in approximately 35% of APLs, and large-scale studies have identified the presence of ITD as an adverse prognostic factor for acute myeloblastic leukemia (AML) patients. Aberrant expressions of surface antigens, such as CD2, CD34, and CD56, have been found in APL, but the implications of this are not well understood. We investigated the incidence of the FLT3/ITD mutation and FLT3/D835 (I836) point mutation in 25 APL patients. Incidence ratios of FLT3/ITD, D835 (I836), and both FLT3/ITD and D835 (I836) were 36%, 36% and 8%, respectively. FLT3/ITD(+) cases showed a predominance of the bcr3 isoform (P=0.008) and M3v morphology (P<0.001). We found that all FLT3/ITD(+) cases expressed CD2 (9 of 9) more frequently than that of FLT3/ITD(-) (1 of 16) (P<0.001), while only one of the CD2(+) cases (1 of 10, 10%) did not harbor FLT3/ITD, and all CD2(+)CD34(+) cases (5 of 5, 100%) harbored FLT3/ITD. In addition, quantitative polymerase chain reaction analysis showed that FLT3 mRNA was more abundantly expressed in FLT3/ITD(+) than that in FLT3/ITD(-) (P=0.025), while there was no difference between D835(I836) (+) and D835(I836)(-) with regards to aberrant surface-antigen expression, expression levels of FLT3 mRNA, M3v morphology, and the bcr3 isoform of PML-RARα mRNA. This study demonstrates that the presence of FLT3/ITD, but not D835 (I836), is closely related to aberrant CD2 expression and high expression levels of FLT3 mRNA. Our findings also suggest that FLT3/ITD as a secondary genetic event may block differentiation at the immature stage of APL.
急性早幼粒细胞白血病（APL）的特征是由t(15;17)(q22;q12)易位产生的特异性PML-RARα融合基因。在大约35%的APL病例中观察到FLT3基因的内部串联重复（ITD），大规模研究已确定ITD的存在是急性髓细胞白血病（AML）患者的不良预后因素。在APL中发现了表面抗原如CD2、CD34和CD56的异常表达，但其意义尚不完全清楚。我们调查了25例APL患者中FLT3/ITD突变和FLT3/D835（I836）点突变的发生率。FLT3/ITD、D835（I836）以及FLT3/ITD和D835（I836）两者的发生率分别为36%、36%和8%。FLT3/ITD(+)病例中bcr3异构体占优势（P=0.008）且具有M3v形态（P<0.001）。我们发现所有FLT3/ITD(+)病例（9/9）比FLT3/ITD(-)病例（1/16）更频繁地表达CD2（P<0.001），而在CD2(+)病例中只有1例（1/10，10%）没有FLT3/ITD，并且所有CD2(+)CD34(+)病例（5/5，100%）都有FLT3/ITD。此外，定量聚合酶链反应分析显示，FLT3 mRNA在FLT3/ITD(+)病例中的表达比在FLT3/ITD(-)病例中更丰富（P=0.025），而在D835(I836) (+)和D835(I836)(-)病例之间，在异常表面抗原表达、FLT3 mRNA表达水平、M3v形态以及PML-RARα mRNA的bcr3异构体方面没有差异。本研究表明，FLT3/ITD的存在而非D835（I836）与CD2异常表达和FLT3 mRNA高表达水平密切相关。我们的研究结果还表明，FLT3/ITD作为继发性遗传事件可能在APL的未成熟阶段阻断分化。
