Aberrant expression and deletion of FHIT gene in leukemias.
FHIT (fragile histidine triad) gene at chromosome 3p14.2 usually expresses at a very low level in human tissue and cells. A high frequency of abnormalities in FHIT gene has been demonstrated in various cancers. FHIT is proposed as a putative tumor-suppressor gene. To evaluate the expression of the FHIT gene in various leukemias, bone marrow or peripheral blood samples from 98 leukemia patients were tested by RT-PCR: 38 from patients with AML-[M(2)(9), M(3)(12), M(4)(8), M(5)(9)], 16 with ALL, and 34 with CML-[CP(20), AP(4), BC(10)] of various FAB types, as well as 10 patients with other hematological malignancies. To detect a deletion in sequencing the FHIT gene, the representative aberrant PCR products were cloned and then sequenced. The results showed that 22/38 (58%) patients with AML, 9/16 (56%) patients with ALL and 19/34 (56%) patients with CML were detectable of aberrant FHIT mRNA transcripts or deletion of FHIT. In 6 (16%) AML patients, 3 (19%) ALL patients, and 5 (15%) CML patients, the wild-type product was absent. Some patient's samples - 6 (42%) AML, 6 (38%) ALL, and 14 (41%) CML revealed aberrant FHIT transcripts in addition to a normal-sized band. Samples from healthy donors (PB, n = 12; BM, n = 5) did not indicate any abnormal expression. Eleven isolated fragments from various patterns of FHIT gene expression were investigated using cDNA sequencing. Sequence analysis revealed deletion of exon 4-8, exon 5-8, and exon 5-6 in various leukemias, as well as the deletion of the full FHIT gene sequence. The fused transcripts included: exon 3 and exon 9, exon 3 and exon 7, exon 4 and exon 9, exon 5 and exon 7. Sequence analysis of aberrant fragments present in samples from an AML and a CML patients was detected for point mutations and insert mutations located in exons 2, 8 and 10, plus a variety of aberrant transcripts. Deletion or aberrant FHIT mRNA transcripts in 50/98 (51%) leukemia patients were found. All samples with aberrant FHIT lacked gene product. A Kaplan-Meier plot of survival in patients with AML in relation to FHIT expression revealed that aberrance or loss of FHIT gene significantly correlated with a low clinical remission rate and poor overall survival.
Department of Oncology, General Hospital of Beijing Military Area of PLA, Beijing 100700, China.
Li
L
Wang
Lu-Jia
LJ
Dong
Fang
F
Tian
Guang-Xian
GX
Liu
Chun-Hai
CH
Li
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D001483:Base Sequence; D017353:Gene Deletion; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000099170:Bis(5'-adenosyl)triphosphatase