TY - JOUR
T1 - Silencing of the tumor suppressor gene FHIT is highly characteristic for MLL gene rearranged infant acute lymphoblastic leukemia
AU - Stam, R W
AU - den Boer, M L
AU - Passier, M M C J
AU - Janka-Schaub, G E
AU - Sallan, S E
AU - Armstrong, S A
AU - Pieters, R
N1 - Funding Information:
Correspondence: Dr ML den Boer, Department of Pediatric Oncology/ Hematology, Erasmus MC/Sophia Children’s Hospital, Room Sp 2456, Dr Molewaterplein 60, PO Box 2060, 3000 CB Rotterdam, The Netherlands. E-mail: [email protected] Financial support: This study was supported by a grant from the Sophia Foundation for Medical Research (SSWO Grant 296) Received 22 August 2005; revised 28 October 2005; accepted 9 November 2005; published online 15 December 2005
PY - 2006/2
Y1 - 2006/2
N2 - MLL rearranged acute lymphoblastic leukemia (MLL) is an aggressive type of acute lymphoblastic leukemia (ALL), diagnosed predominantly in infants (<1 years of age). Since current chemotherapy fails in >50% of patients with MLL, new therapeutic strategies are desperately needed. For this, understanding the biological features characterizing MLL is necessary. Analysis of gene expression profiles revealed that the expression of the tumor suppressor gene FHIT is reduced in children with MLL rearranged ALL as compared to ALL patients carrying germ line MLL. This finding was confirmed by quantitative real-time PCR. In 100% of the infant MLL cases tested, methylation of the FHIT 5'CpG region was observed, resulting in strongly reduced mRNA and protein expression. In contrast, FHIT methylation in infant and non-infant ALL patients carrying germ line MLL was found in only approximately 60% (P< or =0.004). FHIT expression was restored upon exposing leukemic cells to the demethylating agent decitabine, which induced apoptosis. Likewise and more specifically, leukemic cell death was induced by transfecting MLL rearranged leukemic cells with expression vectors encoding wild-type FHIT, confirming tumor suppressor activity of this gene. These observations imply that suppression of FHIT may be required for the development of MLL, and provide new insights into leukemogenesis and therapeutic possibilities for MLL.
AB - MLL rearranged acute lymphoblastic leukemia (MLL) is an aggressive type of acute lymphoblastic leukemia (ALL), diagnosed predominantly in infants (<1 years of age). Since current chemotherapy fails in >50% of patients with MLL, new therapeutic strategies are desperately needed. For this, understanding the biological features characterizing MLL is necessary. Analysis of gene expression profiles revealed that the expression of the tumor suppressor gene FHIT is reduced in children with MLL rearranged ALL as compared to ALL patients carrying germ line MLL. This finding was confirmed by quantitative real-time PCR. In 100% of the infant MLL cases tested, methylation of the FHIT 5'CpG region was observed, resulting in strongly reduced mRNA and protein expression. In contrast, FHIT methylation in infant and non-infant ALL patients carrying germ line MLL was found in only approximately 60% (P< or =0.004). FHIT expression was restored upon exposing leukemic cells to the demethylating agent decitabine, which induced apoptosis. Likewise and more specifically, leukemic cell death was induced by transfecting MLL rearranged leukemic cells with expression vectors encoding wild-type FHIT, confirming tumor suppressor activity of this gene. These observations imply that suppression of FHIT may be required for the development of MLL, and provide new insights into leukemogenesis and therapeutic possibilities for MLL.
KW - Acid Anhydride Hydrolases/genetics
KW - Cell Line, Tumor
KW - CpG Islands/genetics
KW - DNA Methylation
KW - Gene Expression Profiling
KW - Gene Rearrangement
KW - Gene Silencing
KW - Histone-Lysine N-Methyltransferase
KW - Humans
KW - Infant
KW - Myeloid-Lymphoid Leukemia Protein/genetics
KW - Neoplasm Proteins/genetics
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
KW - RNA, Messenger/genetics
KW - Reverse Transcriptase Polymerase Chain Reaction
UR - http://www.scopus.com/inward/record.url?scp=31444446830&partnerID=8YFLogxK
U2 - 10.1038/sj.leu.2404074
DO - 10.1038/sj.leu.2404074
M3 - Article
C2 - 16357833
SN - 0887-6924
VL - 20
SP - 264
EP - 271
JO - Leukemia
JF - Leukemia
IS - 2
ER -