Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML–BFM and DCOG study groups

Damm, Frédérik; Thol, Felicitas; Hollink, Iris H.I.M.; Zimmermann, Martin; Reinhardt, Katarina; Heuvel‐Eibrink, Marry M. van den; Zwaan, C. Michel; Haas, Valérie de; Creutzig, Ursula; Klusmann, Jan‐Henning; Krauter, Jürgen; Heuser, Michael; Ganser, Arnold; Reinhardt, Dirk; Thiede, Christian

doi:10.1038/leu.2011.142

Cited by 74 publications

(65 citation statements)

References 42 publications

(62 reference statements)

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“…30 Likewise, low S100A8 and S100A9 expression has been shown to correlate with a good prognosis in childhood AML patients carrying IDH1/2 mutations. 31 Therefore, we asked whether high-level S100A8 and S100A9 expression is also associated with a poor prognosis in MLL-rearranged infant ALL. For this, we divided patient samples into two groups either expressing high or low levels of S100A8 and S100A9 based on our quantitative RT-PCR data, using the median S100A8/S100A9 expression levels as cut-off values.…”

Section: Resultsmentioning

confidence: 99%

“…31 Similarly, Nicolas et al 30 demonstrated that high-level expression S100A8 represents poor prognostic marker in de novo pediatric AML. In concordance, our data shows that high-level S100A8/ S100A9 expression not only correlates with glucocorticoid resistance, but in itself seems to accurately predict an inferior outcome in MLL-rearranged infant ALL.…”

Section: Discussionmentioning

confidence: 97%

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Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

et al. 2012

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MLL-rearranged acute lymphoblastic leukemia (ALL) in infants is characterized by a poor clinical outcome and resistance to glucocorticoids (for example, prednisone and dexamethasone). As both the response to prednisolone in vitro and prednisone in vivo are predictive for clinical outcome, understanding and overcoming glucocorticoid resistance remains an essential step towards improving prognosis. Prednisolone-induced apoptosis depends on glucocorticoid-evoked Ca 2 þ fluxes from the endoplasmic reticulum towards the mitochondria. Here, we demonstrate that in MLL-rearranged infant ALL, over-expression of S100A8 and S100A9 is associated with failure to induce free-cytosolic Ca 2 þ and prednisolone resistance. Furthermore, we demonstrate that enforced expression of S100A8/S100A9 in prednisolone-sensitive MLL-rearranged ALL cells, rapidly leads to prednisolone resistance as a result of S100A8/S100A9 mediated suppression of prednisolone-induced free-cytosolic Ca 2 þ levels. In addition, the Src kinase inhibitor PP2 markedly sensitized MLL-rearranged ALL cells otherwise resistant to prednisolone, via downregulation of S100A8 and S100A9, which allowed prednisolone-induced Ca 2 þ fluxes to reach the mitochondria and trigger apoptosis. On the basis of this novel mechanism of prednisolone resistance, we propose that developing more specific S100A8/S100A9 inhibitors may well be beneficial for prednisolone-resistant MLL-rearranged infant ALL patients.Leukemia ( Keywords: prednisolone resistance; S100A8 and S100A9; calcium signaling; MLL-rearranged infant leukemia INTRODUCTIONSince the early 1960s, treatment results for childhood acute lymphoblastic leukemia (ALL) began to improve steadily and continued to progress ever since. Consequently, the survival chances for childhood ALL, in general, nowadays exceed 85%. 1 Unfortunately, this tremendous step forward has not been equally beneficial for all patients. This is especially true for infants (o1 year of age) with ALL carrying leukemia-specific chromosomal translocations involving the MLL gene, which occur in B80% of the infant ALL cases. 2,3 Depending on the treatment protocol, survival chances for MLL-rearranged infant ALL patients are at best B40%. 3 Considerably contributing to this poor outcome is cellular resistance to multiple chemotherapeutic drugs, in particular to glucocorticoids like prednisone and dexamethasone, which form the cornerstone of childhood ALL treatment regimes. Prednisolone (the biologically active metabolite of prednisone) dosages needed to eliminate 50% of infant ALL cells in vitro typically are B500 --fold higher than the dosages required to eradicate similar amounts of precursor B-ALL cells from children older than one year of age (that is, non-infants). 4 Moreover, approximately 30% of infants with MLL-rearranged ALL show a poor prednisone response in vivo, compared with only B10% of non-infant pediatric precursor B-ALL cases. 5 As the in vitro prednisolone response and the prednisone response in vivo represent important prognostic factors, 6 --8 ...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

et al. 2012

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“…[16][17][18] Mutation of DNMT3A, which encodes a DNA methyltransferase, was first identified by wholegenome sequencing in an AML patient with normal karyotype and detected in 22% of adult patients with de novo AML, especially those in the intermediate-risk cytogenetic group.…”

Section: Introductionmentioning

confidence: 99%

Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A

Liang

Liu

Yang

et al. 2013

Blood

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Key Points• A comprehensive study of 19 gene mutations and their cooperation, including the first report of ASXL1 and TET2 mutations in pediatric AML.• The development of pediatric AML requires fewer gene mutations than adult AML.Gene mutations involving epigenetic regulators recently have been described in adult acute myeloid leukemia (AML). Similar studies are limited in children. We analyzed gene mutations and cooperation in pediatric AML with special reference on mutated epigenetic regulators. Nineteen gene mutations, including 8 class I genes, 4 class II genes, WT1 and TP53 (class III), and 5 epigenetic regulator genes (class IV), were analyzed in 206 children with de novo AML. Mutational analysis was performed with polymerase chain reaction2 based assay followed by direct sequencing. One hundred seventeen of 206 patients (56.8%) had at least one mutation: 51% class I, 13% class II, 6.8% class III, and 5.6% class IV. FLT3-internal tandem duplication was most frequent, and 29% of patients had more than one gene mutation. Two patients carried ASXL1 mutations, both with t(8;21), 2 had DNMT3A mutations, 2 had IDH1 mutations, 1 had IDH2 mutation, and 3 had TET2 mutations. Both patients with IDH1 mutations had AML-M0 subtype and MLL-partial tandem duplication. Cooperating mutations with mutated epigenetic regulators were observed in 8 of 10 patients. We conclude that mutated epigenetic regulators were much less than those in adult AML but with frequent cooperating mutations. ASXL1, TET2, and IDH1 mutations were associated with specific genetic subtypes. (Blood. 2013;121(15):2988-2995 IntroductionComprehensive analyses in de novo childhood acute myeloid leukemia (AML) of gene mutations involving epigenetic regulators have been limited. The ASXL1 (additional sex comb-like 1) gene mapping to chromosome 20q acts as a cofactor of retinoic acid receptor via binding to steroid receptor coactivation-1 and belongs to enhancer of trithorax and polycomb genes that can both activate and repress the HOX gene.1,2 Very recently, it has been demonstrated that ASXL1 loss-of-function mutations result in the loss of polycomb repressive complex 22mediated histone H3 lysine 27 trimethylation, which promotes myeloid leukemia transformation.3 ASXL1 mutations conferred a poor outcome in adult AML, 4,5 but there have been no reports of ASXL1 mutations in childhood AML. TET proteins encode a-ketoglutarate-dependent oxygenases, which are involved in the conversion of 5-methylcytosine to 5-hydroxymethylcytosine. 6 TET2 protein is important for normal myelopoiesis, and disruption of TET2 enzymatic activity results in altered DNA methylation and favors myeloid neoplasm transformation.7 IDH1 and IDH2 mutations convert a-ketoglutarate to 2-hydroxyglutarate, which disrupts TET2 function. 8,9 Somatic mutations of TET2 were identified with microdeletion at 4q24 in myeloid neoplasms by the use of high-resolution single-nucleotide polymorphism microarrays.10,11 TET2 mutations were detected in adult AML with a frequency ranging from 7% to 23%, but t...

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“…Most of these studies focused on the relevance of mutations in a single gene and mutations were detected in 1-4% of the patients. [9][10][11][12][13] Although no significant statements can be made since study cohorts were quite heterogeneous, most mutations seemed to occur in cytogenetically normal (CN) AML, a subgroup that comprises 20-25% of all pediatric AML. This distribution corresponds to adult AML data in which most epigenetic regulator gene mutations were also identified in CN patients.…”

Section: 8mentioning

confidence: 99%

Mapping epigenetic regulator gene mutations in cytogenetically normal pediatric acute myeloid leukemia

et al. 2014

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Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML–BFM and DCOG study groups

Cited by 74 publications

References 42 publications

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A

Mapping epigenetic regulator gene mutations in cytogenetically normal pediatric acute myeloid leukemia

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