Aberrant FHIT transcripts in acute myeloid leukaemia

Lin, Pei; Liu, Ta-Chih; Chang, Jan‐Gowth; Chen, Tyen-Po; Lin, Sheng-Fung

doi:10.1046/j.1365-2141.1997.4223235.x

Cited by 18 publications

(12 citation statements)

References 28 publications

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“…Decreased or altered expression of the FHIT gene has been reported in fresh leukaemia samples and cell lines (Lin et al, 1997;Sugimoto et al, 1997), and loss of normal FHIT function is considered to be involved in the development of at least some human leukaemias (Sugimoto et al, 1997). The FHIT transcript lacking exon 3 to 6 was present in 14 of 14 AML, 11 of 13 CML, 5 of 5 ALL and 3 of 5 chronic lymphocytic leukaemia, but in only 1 of 25 normal control samples.…”

Section: Discussionmentioning

confidence: 98%

“…This was proposed as specific and frequent changes in leukaemia samples. Lin et al (1997) found that 27% AML patients showed the aberrant transcripts and most of them lacked exons 4 to 6. With the subcloning technique, we In the present study, we found that the frequency of loss of normal FHIT expression (pattern III or IV) varied in each type of leukaemia cell line.…”

Section: Discussionmentioning

confidence: 99%

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Pattern ofFHIT gene expression in normal and leukaemic cells

et al. 1999

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Pattern ofFHIT gene expression in normal and leukaemic cells

et al. 1999

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“…For example, aberrant FHIT transcription has been reported in acute myeloid leukemia and ALL. 36,37 The FHIT protein has been implicated as a tumor suppressor gene, but the exact biologic function is not known. 38,39 FHIT was 1 of only 4 discriminating purine pathway genes expressed at a higher level in ALL with the TEL-AML1 fusion.…”

Section: Discussionmentioning

confidence: 99%

Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis

Zaza

Yang

Kager

et al. 2004

Blood

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Because de novo purine synthesis (DNPS) is a target of widely used antileukemic agents (eg, methotrexate, mercaptopurine), we determined the rate of DNPS and the expression of genes involved in purine metabolism in different subtypes of acute lymphoblastic leukemia (ALL). Among 113 children with newly diagnosed ALL, lymphoblasts with the TEL-AML1 translocation had significantly lower DNPS than all other genetic subtypes of B-lineage ALL or T-lineage ALL (352 ؎ 57 versus 1001 ؎ 31 or versus 1315 ؎ 76 fmol/nmol/h, P < .0001). By assessing the expression of 82 genes involved in purine metabolism (KEGG pathway database) in ALL blasts from 38 patients with B-lineage ALL (14 with TEL-AML1, 24 without), we identified 16 genes that were differentially expressed in TEL-AML1-positive and TEL-AML1-negative ALL (P < .001, false discovery rate [FDR] ‫؍‬ 5%). The pattern of expression of these 16 genes discriminated TEL-AML1-positive ALL with a true accuracy of 84% in an independent test set (n ‫؍‬ 17, confidence interval 70% to 94%, P < .001). Western blots of selected genes documented corresponding levels of the proteins encoded. Differentially expressed genes included HPRT, IMPDH, PAICS, and GART, all of which were expressed at a significantly lower level in TEL-AML1 ALL. These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism. ( IntroductionPediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising different immunophenotypes and various genetic subtypes caused by chromosomal translocations with aberrant gene fusions and inappropriate expression of oncogenes. These genetic abnormalities have important prognostic and therapeutic implications, but the underlying mechanisms are not fully understood. 1 De novo purine synthesis (DNPS) is higher in ALL cells compared with normal bone marrow cells and peripheral blood lymphocytes, and T-lineage ALL has higher DNPS than B-lineage ALL. 2,3 It is not known, however, whether DNPS differs among the genetic subtypes of B-lineage ALL.Nucleotides play a key role in many biochemical processes related to their importance as DNA and RNA precursors, energy carriers, coenzyme components, and metabolic regulators. 4 Cells obtain purine nucleotides through 2 separate metabolic pathways, de novo purine synthesis and salvage of extracellular purine bases and nucleotides. DNPS and several enzymes involved in the purine metabolism pathway are important targets for antimetabolites (eg, mercaptopurine and methotrexate) that are the cornerstone of continuation therapy for childhood ALL. 1 DNPS is a complex pathway in which nucleotides are synthesized from amino acids and tetrahydrofolate in a multienzymatic process, starting with phosphoribosyl pyrophosphate (PRPP), primarily formed from ribose-5-phosphate (from the pentose phosphate pathway) and adenosine triphosphate (ATP). 4 Previous studies have shown that the pattern of gene expression in ALL blasts differs among ...

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“…6 In hematological malignancies, aberrant FHIT transcripts have been reported in acute and chronic leukemia, although it was demonstrated that those aberrant transcripts were observed in both normal and malignant hematopoietic cells. [7][8][9][10] In contrast, the loss or reduced expression of FHIT protein was restricted to malignant hematopoietic cells, while neither loss nor reduction was associated with progression, response to therapy or prognosis in chronic myeloid leukemia (CML) and prognosis in acute lymphocytic leukemia (ALL). 11,12 These results indicated that inactivating alterations of the FHIT gene, which result in the loss or reduced expression of its product, may be involved in the pathogenesis of hematological malignancies, but the clinical significance was not well documented.…”

Section: Introductionmentioning

confidence: 99%

Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome

et al. 2005

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To clarify the role of fragile histidine triad (FHIT) in hematological malignancies, we examined the methylation status and the expression level of the FHIT gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells in comparison with the methylation of the p15 INK4B gene. The FHIT methylation was found in 13 of 94 (13.8%) AML and 22 of 40 (55.0%) MDS cases, but not in normal mononuclear cells (MNCs). Both the frequency and density of methylation increased in the advanced-stages MDS and the relapsed AML cases. Although FHIT and p15 INK4B methylations were not correlated in MDS and AML, increased FHIT methylation at the relapse in AML was associated with p15 INK4B methylation. The median expression level in AML was significantly higher than in normal MNCs, although the median expression level in those with methylation was significantly lower than in those without methylation. Furthermore, the methylation level at relapse was significantly higher than at diagnosis in AML. These results suggested that FHIT methylation was accumulated through the disease progression of MDS and AML, and the role of the FHIT gene as a tumor suppressor seemed different in AML and MDS.

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Aberrant FHIT transcripts in acute myeloid leukaemia

Cited by 18 publications

References 28 publications

Pattern ofFHIT gene expression in normal and leukaemic cells

Pattern ofFHIT gene expression in normal and leukaemic cells

Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis

Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome

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