Expression of high Km 5′-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia

Galmarini, Carlos M.; Graham, Kathryn; Thomas, Xavier; Calvo, Fabien; Rousselot, Philippe; Jafaari, Assia El; Cros, Emeline; Mackey, John R.; Dumontet, Charles

doi:10.1182/blood.v98.6.1922

Cited by 78 publications

(48 citation statements)

References 39 publications

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“…20 Other cellular mechanisms that might contribute to leukemia resistance and poor outcome and which might be incorporated in such analyses include expression of anti-apoptotic proteins 21,22 or high 5′nucleotidase activities. 23 Pertinent to our observation are the reliability of both detection and quantification of MRD. We have taken this into account firstly by carefully establishing that the CD34 negative AML samples (defined as Ͻ1% CD34 + ) used to define transplant CD34 + cells as normal, remained CD34-negative at relapse.…”

Section: Discussionmentioning

confidence: 99%

High percentage of CD34-positive cells in autologous AML peripheral blood stem cell products reflects inadequate in vivo purging and low chemotherapeutic toxicity in a subgroup of patients with poor clinical outcome

et al. 2003

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In this study, a high CD34% in autologous peripheral blood stem cell (PBSC) products from 71 AML patients was associated directly with a high relapse rate (P = 0.006) and inversely with disease-free survival (P = 0.003), irrespective whether patients were transplanted or not. The relapse rate at 12 months was 67% in a group with Ͼ0.8% CD34 + cells and 34% in a group with р0.8% CD34 + cells. Although the percentage of malignant CD34 + cells in the CD34 + compartment in the relapses of the first group was not high (median 8%), the total number of malignant cells as a percentage of WBC was about 13 times higher than for the patients remaining Ͼ12 months in remission. When all patients evaluable were taken together, this frequency of malignant cells correlated strongly with disease-free survival (P Ͻ 0.001). Both this massive mobilization of normal CD34 + cells and high frequency of malignant cells in the subgroup of patients with CD34 Ͼ0.8% and relapse within 12 months indicate an insufficient in vivo purging, as well as low chemotherapeutic bone marrow toxicity. This was confirmed by an inverse correlation between hypoplasia period after the induction therapy and CD34% in PBSC products (P Ͻ 0.002). It is concluded that a subgroup of patients has been identified that might benefit from a more intensive chemotherapeutic treatment.

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Section: Discussionmentioning

confidence: 99%

High percentage of CD34-positive cells in autologous AML peripheral blood stem cell products reflects inadequate in vivo purging and low chemotherapeutic toxicity in a subgroup of patients with poor clinical outcome

et al. 2003

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“…156 Finally, high 5NT expression in blast cells was shown to be an independent prognostic factor for poor outcome in 108 AML patients after ara-Ccontaining regimens. 157 The balance between dCK and 5NT might predict drug toxicity, since strongly increased 5NT activity combined with reduced dCK activity was observed in a human leukaemic cell line, resistant to ara-C and dFdC. 158 Apart from resistance to nucleoside analogues caused by aberrant drug metabolism, altered drug transport may cause decreased chemosensitivity.…”

Section: Jg Maring Et Almentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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“…In AML, we have reported that patients whose blasts expressed high K m 5Ј-NU mRNA had shorter time-to-relapse and overall survival than patients with no expression. 144 However, due to the multiplicity of 5Ј-NU activities, and the limited ability of classical biochemical methodology to differentiate between these activities, the particular 5Ј-NU enzyme(s) with the largest impact on clinical resistance to NA have not yet been convincingly identified. 145 …”

Section: ј-Nucleotidasementioning

confidence: 99%