In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype

Woerden, N. L. Ramakers-Van; Beverloo, H. Berna; Veerman, A. J. P.; Camitta, Bruce M.; Loonen, A. H.; Wering, E. R. Van; Slater, Rosalyn; Harbott, Jochen; Boer, Monique L. den; Ludwig, Wolf‐Dieter; Haas, OA; Janka‐Schaub, Gritta; Pieters, Rob

doi:10.1038/sj.leu.2403253

Cited by 79 publications

(78 citation statements)

References 32 publications

(23 reference statements)

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“…20 MLLrearranged infant ALL cells bearing an RAS mutation at diagnosis appeared significantly (P<0.05) more resistant to both glucocortocoids (Figure 2A and B). A comparable trend was only observed for t(4;11)-positive samples, although the differences did not reach statistical significance ( Figure 2C and D).…”

Section: Drug Resistance Of Ras-mutated Infant All Patientsmentioning

confidence: 96%

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

et al. 2013

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). Finally, we demonstrate that RAS mutations, and not the lack of Homeobox gene A9 expression nor the expression of AF4-MLL are associated with poor outcome in t(4;11)-rearranged infants. We conclude that the presence of RAS mutations in Mixed Lineage Leukemiarearranged infant acute lymphoblastic leukemia is an independent predictor for a poor outcome. Therefore, future risk-stratification based on abnormal RAS-pathway activation and RAS-pathway inhibition could be beneficial in RAS-mutated infant acute lymphoblastic leukemia patients. Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

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Section: Drug Resistance Of Ras-mutated Infant All Patientsmentioning

confidence: 96%

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

et al. 2013

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“…The sensitivity of the cells to each enzyme was tested with the MTT assay. 9 The dephosphorylated GA, which possesses normal enzyme activity but enters the NIH-3T3 cells less effectively than does phosphorylated GA, 4 The T-lymphoblastoid CCRF-CEM cell line was less sensitive to all of the enzymes. After 96 h incubation in the presence of 100 U/l of dephosphorylated GA or GA, the viability of the CCRF-CEM cells was 60 or 70%, respectively (Figure 2b).…”

Section: Depletion Of L-asparagine Supply and Apoptosis Of Leukemia Cmentioning

confidence: 99%

“…The sensitivity of the cells to each enzyme was tested with the MTT assay. 9 The dephosphorylated GA, which possesses normal enzyme activity but enters the NIH-3T3 cells less effectively than does phosphorylated GA, 4 was used to figure out whether there was any difference between the native phosphorylated and dephosphorylated GA in inducing the death of the leukemic cells. The enzyme concentrations that caused a 50% growth inhibition of SUP-B15 cells (IC 50 values) in cell culture for GA, dephosphorylated GA, ErAII and EcAII were 15, 16, 8 and 5 U/l, respectively (Figure 2a).…”

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confidence: 99%

Depletion of L-asparagine supply and apoptosis of leukemia cells induced by human glycosylasparaginase

2009

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ReferencesA lysosomal enzyme glycosylasparaginase (GA; aspartylglucosaminidase; EC 3.5.1.26) hydrolyzes the N-glycosidic carbohydrate-to-protein linkage region, aspartylglucosamine, to L-aspartic acid and l-amino-N-acetylglucosamine through a reaction mechanism similar to L-asparaginase. 3 Glycosylasparaginase is transported in active form into various non-neuronal cell types, including Epstein-Barr virus-transformed (EBV) glycosylasparaginase-deficient lymphoblasts, and it effectively corrects the metabolic defects in glycosylasparaginase-deficient cell lines 4 and mice. 5 The finding that human glycosylasparaginase also hydrolyzes L-asparagine to L-aspartic acid and ammonia-like bacterial L-asparaginases 6 without any L-glutaminase activity 3 led us to investigate its potential cytotoxic activity toward leukemia cells that are dependent on their external supply of L-asparagine. We investigated the ability of human recombinant GA to deplete the intra-and extracellular Asn reservoirs in vitro using EBVtransformed glycosylasparaginase-deficient lymphoblasts from an Letters to the Editor 1167 Leukemia aspartylglycosaminuria patient. 4 Lymphoblasts were continuously grown in an RPMI-1640 (HyClone, Logan, Utah, USA) medium supplemented with 15% of fetal calf serum (BioClear, Wiltshire, UK), 2 mM L-glutamine (HyClone) and 1.5-2.0 mM L-asparagine (Fluka Chemie AG, Buchs, Switzerland) and various concentrations of either GA or Erwinia L-asparaginase (Erwinase, ErAII) for 24 h. The kinetic parameters of the enzymes for the hydrolysis of L-asparagine were determined by a spectrophotometric method as described. 7,8 At pH 7.5, the K m of glycosylasparaginase, Erwinia L-asparaginase and Escherichia coli L-asparaginase was 538, 90 and 130 mM and V max 1.49, 16 and 23 mM/min, respectively. One unit of enzyme causes hydrolysis of 1 mmol of L-asparagine per minute under standard conditions.The depletion of the extracellular Asn concentration in the culture medium from 2.3 to 0.2 mmol/l in the presence of 10 or 40 U/l of glycosylasparaginase or 10 U/l of ErAII took 18, 4 and 4 h, respectively. In the presence of 1500 U/l of ErAII, similar Asn concentration decrease occurred within 5 min. The Asn level in the cell culture medium remained unchanged at approximately 2 mmol/l in the absence of either glycosylasparaginase or ErAII (Figure 1a).To determine whether the enzymes can deplete the intracellular Asn reservoirs of EBV-transformed lymphoblasts, we analyzed both the Asn concentration and the enzyme activity inside the cells during the incubation. In the presence of 10 or 40 U/l of glycosylasparaginase or 10 U/l of ErAII in the cell culture medium, the Asn concentration inside the GA-deficient cells first increased within the first 2 h of incubation from the initial approximately 80 nmol/mg protein and then decreased below 6 nmol/mg protein during the next 16-18, 6 or 10-12 h, respectively (Figure 1b). In the presence of 1500 U/l of ErAII in the culture medium, the intracellular Asn concentration decreased from 89 to 14 nmol/m...

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“…Late relapses of TEL-AML1-positive ALL are very rare in the Dana Farber chemotherapy protocol that includes high-dose L-asparaginase as part of the intensification regime (McLean et al, 1996). Correspondingly, ALL blast cells with TEL-AML1 are known to be selectively sensitive in vitro to this drug (Ramakers-van Woerden et al, 2000).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

2004

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Balanced chromosomal translocations are frequently associated with haematopoietic neoplasms and often involve genes that encode transcription factors, which play critical roles in normal haematopoiesis. Fusion oncoproteins that arise from chimeric genes generated by such translocations are usually stable and consistent molecular markers for a given disease subtype and contribute to the leukaemogenic processes. The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in paediatric cancer, occurring in approximately 25% of common (c) B-cell precursor acute lymphoblastic leukaemia (cALL) cases. The rearrangement results in the in-frame fusion of the 5 0 region of the ETS-related gene, TEL (ETV6), to almost the entire AML1 (RUNX1) locus and is associated with favourable prognosis following conventional therapeutic strategies. We discuss here the prenatal origins of the TEL/AML1 translocation as an initiating mutation, the role of TEL-AML1 in cellular transformation and the molecular mechanisms by which the chimeric protein imposes altered patterns of gene expression.

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In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype

Cited by 79 publications

References 32 publications

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

Depletion of L-asparagine supply and apoptosis of leukemia cells induced by human glycosylasparaginase

Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

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