Frequent deletion in the methylthioadenosine phosphorylase gene in T- cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy

Batova, Ayse; Diccianni, Mitchell B.; Nobori, Tsutomu; Vu, Tien P.; Yu, John; Bridgeman, Louis J.; Yu, Alice L.

doi:10.1182/blood.v88.8.3083.bloodjournal8883083

Cited by 59 publications

(37 citation statements)

References 18 publications

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“…MTAP deficiency was first reported in cell lines (Kamatani et al, 1982) and T-ALL (Traweek et al, 1988), but molecular explanations could not be given at that time. MTAP co-deletion has now been evidenced in many tumors with CDKN2A deletion, and a recurrent breakpoint has been observed between exons 4 and 5 (Batova et al, 1996). We found a bi-allelic deletion of MTAP in 38% of the T-ALLs studied, corresponding to 53% of cases with a CDKN2A deletion.…”

Section: Discussionmentioning

confidence: 49%

“…MTAP encodes meth-ylthioadenosine phosphorylase, a ubiquitous enzyme involved in purine and methionine salvage metabolism. It has been suggested that the loss of MTAP activity could make cancer cells more sensitive to drugs that interfere with purine metabolism (Batova et al, 1996). Therefore, in addition to the prognosis associated with CDKN2A inactivation in ALL, the extent of 9p21 deletion could be of importance for the treatment response.…”

Section: Introductionmentioning

confidence: 99%

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CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

Bertin

Acquaviva

Mirebeau

et al. 2003

Genes Chromosomes & Cancer

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Deletion of the 9p21 chromosomal region is frequently found in childhood acute lymphoblastic leukemia (ALL). The target of these deletions is CDKN2A, a gene encoding both p16(INK4a) and p14(ARF). However, contiguous genes such as CDKN2B, encoding p15(INK4b), or MTAP, encoding methylthioadenosine phosphorylase, can be included in the deletions. Gene dosage by use of real-time PCR has recently been proposed as a promising technical option for the diagnosis of deletions. However, its reliability and its capacity to detect mono-allelic deletions in tumor samples are controversial. To evaluate the frequency and extent of deletions in 284 children with ALL, we devised a real-time PCR assay for CDKN2A, CDKN2B exons 1beta and 3, and MTAP gene dosage and validated it by comparison with loss-of-heterozygosity analysis. We show that, if several controls and adjustments are performed, real-time PCR can provide a reliable test for mono- and bi-allelic deletions in ALL. We propose a strategy that overcomes the major caveats of such a dosage in tumor samples: aneuploidy and contamination by normal cells. By use of this assay, we found bi-allelic deletions in 58 and 17% of T- and B-lineage ALL, respectively. Mono-allelic deletion was observed in about 15% of cases, stressing the importance of their detection in ALL. CDKN2B and/or MTAP co-deletions were highly variable in both T- and B-lineage ALL, making ALL with 9p21 a rather heterogeneous group. Because proteins encoded by these genes might influence the response to treatment, the prognosis of 9p21-deleted ALL could vary according to the extent of the deletion.

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Section: Discussionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

Bertin

Acquaviva

Mirebeau

et al. 2003

Genes Chromosomes & Cancer

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“…One of these is MTAP (methylthioadenosine phosphorylase), which is located close to CDKN2A and CDKN2B and is considered a functional tumor-suppressing gene that encodes a key enzyme in the catabolism of methylthioadenosine, 16,18 and the loss of microRNA-31 (hsa-miR-31), which is also located near CDKN2A, is associated with defects in the p53 pathway. 19 It has been reported that the CDKN2A/B deletion only occurs in patients with disease entities described as being aggressive in the WHO classification of cutaneous lymphomas, and so the loss of alterations are significantly associated with a poor response to treatment and poor outcomes in terms of OS and disease-free survival.…”

Section: Discussionmentioning

confidence: 99%

Array‐based CGH of primary cutaneous CD8+ aggressive EPIDERMO‐tropic cytotoxic T‐cell lymphoma

Fanoni

Corti

Violetti

et al. 2018

Genes Chromosomes & Cancer

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Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T‐cell lymphoma (pcAECyTCL) is a rare provisionally categorized cutaneous lymphoma characterized by an aggressive course. Its pathogenesis and molecular mechanisms are still unknown, and only two individual cases have so far been molecularly characterized. The aim of this study was to define the pattern of numerical chromosomal alterations in tumor samples taken from 20 patients with pcAECyTCL at the time of diagnosis by means of array‐comparative genomic hybridization (a‐CGH). a‐CGH detected numerous genomic aberrations in all the patients and, putting these together as a whole, they affected all the chromosomes. However, no specific profile of recurrent copy number alterations (CNAs) was found. Most of the gains involved regions previously described in other aggressive cutaneous lymphomas such as 7q, 8q24.3, and 17q, whereas the most significant CNA was the loss of 9p21.3 (CDKN2A–CDKN2B), which has already been found in a variety of malignant tumors and is associated with aggressive cutaneous T‐cell lymphomas. In brief, CGH analysis revealed a large number of CNAs with only few recurring regions that probably do not represent driving events. The genomic instability found in this aggressive variant of cutaneous lymphoma may therefore be a secondary event but, at the time of the diagnosis of pcAECyTCL, the genomic integrity of tumor cells is already compromised.

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“…2 Cells with loss of MTAP gene function become dependent on de-novo adenosine synthesis, suggesting that these tumours become highly sensitive to treatment with inhibitors of adenosine synthesis. 3 We have shown previously that allelic deletions are very frequent at 9p21 in laryngeal squamous cell carcinoma (LSCC), 4 and others have shown that MTAP allelic losses occur in 62% of oral carcinomas. 5 Loss of MTAP can be associated 6 or not associated 7 with CDKN2A loss.…”

Section: Introductionmentioning

confidence: 92%

Methylthioadenosine phosphorylase inactivation depends on gene deletion in laryngeal squamous cell carcinoma

et al. 2012

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Conde L, Vilaseca I, Alós L, Bernal‐Sprekelsen M, Cardesa A & Nadal A  (2012) Histopathology Methylthioadenosine phosphorylase inactivation depends on gene deletion in laryngeal squamous cell carcinoma Aims: Methylthioadenosine phosphorylase (MTAP) is an essential enzyme for the methionine and adenosine salvage pathway in normal cells, frequently inactivated in many different human cancers. MTAP status could be important for tumour cell sensitivity to adjuvant chemotherapy. To our knowledge, there have been no reports to date on MTAP status in laryngeal carcinoma. Methods and results: A series of 31 laryngeal squamous cell carcinomas was investigated for MTAP mRNA expression using reverse transcription and quantitative polymerase chain reaction (qPCR), as well as for MTAP gene deletion and/or promoter hypermethylation using qPCR and methylation‐specific PCR, respectively. Low MTAP mRNA expression was found in 32% of cases, and was associated with MTAP gene deletion (in 70%; P < 0.001) but not with MTAP promoter hypermethylation, indicating that, in this tumour, gene deletion is the main mechanism for MTAP inactivation. Neither low mRNA expression nor gene deletion was associated with any of the clinicopathological parameters investigated. Conclusion: Given the significance of MTAP status for cell sensitivity to different chemotherapeutic regimens, our results suggest that determination of MTAP inactivation should be taken into consideration in managing laryngeal squamous cell carcinomas.

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Frequent deletion in the methylthioadenosine phosphorylase gene in T- cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy

Cited by 59 publications

References 18 publications

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

Array‐based CGH of primary cutaneous CD8+ aggressive EPIDERMO‐tropic cytotoxic T‐cell lymphoma

Methylthioadenosine phosphorylase inactivation depends on gene deletion in laryngeal squamous cell carcinoma

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