MLL gene rearrangements have no direct impact on Ara-C sensitivity in infant acute lymphoblastic leukemia and childhood M4/M5 acute myeloid leukemia

Stam, Ronald W.; Hubeek, Isabelle; Boer, Monique L. den; Buijs-Gladdines, Jessica; Creutzig, U.; Kaspers, Gertjan J. L.; Pieters, Rob

doi:10.1038/sj.leu.2404031

Cited by 10 publications

(17 citation statements)

References 5 publications

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“…In contrast however, no protective effect of MLL -knockdown was seen for ARAC or MTX in the present study. Whilst one might expect that suppression of DNA-damage response pathways should increase resistance to both of these agents, it is interesting to note that, unlike GCs, elevated resistance to neither of these drugs is associated with MLL -rearrangement [32,33]; infants in fact are known to be generally more sensitive to ARAC [8,32]. There may therefore be some unexplained insult specificity in the role of MLL in mediating responses to DNA-damage.…”

Section: Discussionmentioning

confidence: 99%

Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia

et al. 2010

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BackgroundRearrangement of the mixed-lineage leukemia gene (MLL) is found in 80% of infant acute lymphoblastic leukemia (ALL) and is associated with poor prognosis and resistance to glucocorticoids (GCs). We have recently observed that GC resistance in T-ALL cell lines is associated with a proliferative metabolism and reduced expression of MLL. In this study we have further explored the relationship between MLL status and GC sensitivity.ResultsNegative correlation of MLL expression with GC resistance in 15 T-ALL cell lines was confirmed by quantitative RT-PCR. The absence of MLL-rearrangements suggested that this relationship represented expression of wild-type MLL. Analysis of MLL expression patterns revealed a negative relationship with cellular metabolism, proliferation and anti-apoptotic transcriptional networks. In silico analysis of published data demonstrated that reduced levels of MLL mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverse clinical outcome in children with MLL-rearranged ALL. RNAi knockdown of MLL expression in T-ALL cell lines significantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wild-type MLL in the control of cellular apoptosis.ConclusionsThe data suggests that reduced expression of wild-type MLL can contribute to GC resistance in ALL patients both with and without MLL-translocations.

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Section: Discussionmentioning

confidence: 99%

Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia

et al. 2010

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“…This has led to the initiation of clinical trials with these inhibitors in adult AML; so far the results are promising. Interestingly, constitutively activated FLT3 also occurs in MLL-rearranged infant ALL patients carrying activating mutations and in MLL-rearranged infant ALL displaying high-level expression of wild-type FLT3 [23,46]. We and others have demonstrated that high-level wild-type FLT3 expression in primary infant MLL-rearranged ALL samples is associated with activated FLT3 and cytotoxic responsiveness to FLT3 inhibitors [47,48].…”

Section: New Therapeutic Strategiesmentioning

confidence: 95%

“…Sensitivity to ara-C in infant ALL appeared not to be directly associated with rearrangements of the MLL gene, as both MLL-rearranged and MLL germline infant ALL cases appeared equally sensitive to this drug in vitro [23]. The ara-C sensitivity is most likely due to the high expression of the human equilibrative nucleoside transporter 1 (hENT1) [24], on which ara-C is mainly dependent to permeate the cell membrane.…”

Section: Drug Resistancementioning

confidence: 98%

Infant acute lymphoblastic leukemia: Lessons learned and future directions

Pieters

2009

Curr Hematol Malig Rep

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Compared with acute lymphoblastic leukemia (ALL) in older children, ALL in infants has a dismal outcome because rearrangements of the mixed-lineage leukemia (MLL) gene occur in about 80% of these patients, leading to an aggressive type of leukemia. With most recent therapies, about 50% long-term event-free survival is achieved, but early bone marrow relapse remains a major problem. Early intensification of chemotherapy and new innovative therapies are necessary to improve outcome. Bone marrow transplantation should be limited to a small subset of well-recognized ALL patients with a very poor prognosis. New genetic and epigenetic insights into the biology of MLL-rearranged ALL suggest new possibilities for therapies.

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“…After entering the cell, AraC is initially phosphorylated to AraCMP by deoxycytidine kinase (dCK) and subsequently converted by downstream nucleotide kinases to its cytotoxic form, AraCTP, which then becomes incorporated into DNA during synthesis and leads to apoptosis ( Fig. 1) (Stam et al, 2006). Although effective, pronounced drug resistance and severe hematopoietic toxicity have become two major side effects of AraC treatment, limiting its application in chemotherapy (Barrios et al, 1987;Klumper et al, 1995;Cros et al, 2004;Fernandez-Calotti et al, 2005;Styczynski, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Although effective, pronounced drug resistance and severe hematopoietic toxicity have become two major side effects of AraC treatment, limiting its application in chemotherapy (Barrios et al, 1987;Klumper et al, 1995;Cros et al, 2004;Fernandez-Calotti et al, 2005;Styczynski, 2007). Several factors such as lower AraC transport activity, reduced dCK activity and high hCDA activity are suggested to be associated with the development of AraC resistance, and accumulating evidence suggests that the latter factor may play a key role in this resistance (Cros et al, 2004;Fernandez-Calotti et al, 2005;Stam et al, 2006). For example, in vitro studies indicate a relationship between hCDA expression and resistance to AraC, and leukemic cells from patients in clinical studies have high hCDA expression levels, especially those of refractory AML patients (Steuart and Burke, 1971;Tattersall et al, 1974;Colly et al, 1987;Onetto et al, 1987;Momparler and Laliberte, 1990;Honma et al, 1991;Neff and Blau, 1996;Schroder et al, 1996Schroder et al, , 1998Jahns-Streubel et al, 1997;Ohta et al, 2004;Yoshida et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Creation of zebularine-resistant human cytidine deaminase mutants to enhance the chemoprotection of hematopoietic stem cells

Ruan

Qiu

Beard

et al. 2016

Protein Engineering, Design and Selection

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Human cytidine deaminase (hCDA) is a biomedically important enzyme able to inactivate cytidine nucleoside analogs such as the antileukemic agent cytosine arabinoside (AraC) and thereby limit antineoplastic efficacy. Potent inhibitors of hCDA have been developed, e.g. zebularine, that when administered in combination with AraC enhance antineoplastic activity. Tandem hematopoietic stem cell (HSC) transplantation and combination chemotherapy (zebularine and AraC) could exhibit robust antineoplastic potency, but AraC-based chemotherapy regimens lead to pronounced myelosuppression due to relatively low hCDA activity in HSCs, and this approach could exacerbate this effect. To circumvent the pronounced myelosuppression of zebularine and AraC combination therapy while maintaining antineoplastic potency, zebularine-resistant hCDA variants could be used to gene-modify HSCs prior to transplantation. To achieve this, our approach was to isolate hCDA variants through random mutagenesis in conjunction with selection for hCDA activity and resistance to zebularine in an Escherichia coli genetic complementation system. Here, we report the identification of nine novel variants from a pool of 1.6 × 10 6 transformants that conferred significant zebularine resistance relative to wild-type hCDA2. Several variants revealed significantly higher K i values toward zebularine when compared with wild-type hCDA values and, as such, are candidates for further exploration for gene-modified HSC transplantation approaches.

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MLL gene rearrangements have no direct impact on Ara-C sensitivity in infant acute lymphoblastic leukemia and childhood M4/M5 acute myeloid leukemia

Cited by 10 publications

References 5 publications

Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia

Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia

Infant acute lymphoblastic leukemia: Lessons learned and future directions

Creation of zebularine-resistant human cytidine deaminase mutants to enhance the chemoprotection of hematopoietic stem cells

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