KOBAYASHI Miyuki The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (60205391)
KOH Katsuyoshi The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (50359618)
HAYASHI Yasuhide Gunma Prefectural Institute of Public Health and Environmental Sciences, Researcher, 技師 (30238133)
井田 孔明 東京大学, 医学部附属病院, 助手 (60313128)
|Budget Amount *help
¥8,800,000 (Direct Cost: ¥8,800,000)
Fiscal Year 2004: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2002: ¥3,500,000 (Direct Cost: ¥3,500,000)
11q23 translocations involving MLL gene are recurrent translocations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). As a partner gene of MLL, we have cloned SEPT6, LCX, LAF4 genes in t(X;11), t(10;11), t(2;11), respectively in pediatric ALL and AML. Expression of approximately 2.3-, 3.1-, and 4.6-kb SEPT6 transcripts was simultaneously detected in fetal lung, liver, and brain, in all of the adult tissues except brain, and in ALL and AML cell lines. However, the expression of an approximately 2.7-kb transcript was detected alone in fetal heart and adult brain. The MLL-SEPT6 fusion gene was analyzed in vitro and in vivo. As a partner gene of NUP98, we have cloned HDXC11, HOXD11, HOXA13 genes in t(11;12), t(2;11), t(7;11), respectively in pediatric AML.
Using oligonucleotide microarray analysis, we identified distinct expression profiles for 23 ALL samples with 11q23 translocations, including t(4;11) (n=15), t(11;19) (N=6), and t(5;11) (n=2), compared with 9 ALL samples with other translocations, including t(12;21) (n=6) and t(1;19) (n=3). Gene expression scores of FLT3, Meis1, and CD44 for samples with MLL rearrangements were particularly high compared with those for other ALL samples. Statistical analysis of the gene expression profiles for the 21 ALL samples with MLL rearrangements at diagnosis revealed two subgroups that exclusively correlated with prognosis but not with any other clinico-pathological factor. The transcription factors CBF2 and CDP were highly expressed in the poor and good prognosis subgroups, respectively. In addition, their downstream target genes were differentially expressed. These findings provide new insights into the biological mechanisms of leukemogenesis and prognosis for pediatric ALL with MLL rearrangements.