Improved treatment results for childhood acute myeloid leukemia in Taiwan

Liang, Der‐Cherng; Chang, Ting‐Tsung; Lin, Kai‐Hsin; Lin, Dong‐Tsamn; Lu, Meng-Yao; Chen, S. H.; Liu, H. C.; Lin, Ming Tsan; Lee, M. T.; Shu, San-Ging; Chang, Te Kau; Chen, Jiann‐Shiuh; Hsiao, Cheng-Chih; Hung, Iou‐Jih; Hsieh, Yuh Lin; Chen, R. L.; Cheng, Shu‐Meng; Chang, Wan-Hui; Lee, C. H.; Lin, K. S.

doi:10.1038/sj.leu.2403979

Cited by 40 publications

(25 citation statements)

References 52 publications

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“…In general, standard induction therapy with combination of anthracycline and cytarabine produced 50% to 75% of complete remission rate in adult AML patients (1)(2)(3). Higher remission rate has been observed in newly diagnosed pediatric AML patients treated with improved chemotherapeutic regimens (11,12). However, f30% to 50% of patients relapse with drug resistant disease.…”

Section: Introductionmentioning

confidence: 99%

Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells

et al. 2008

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To understand the mechanism of cellular resistance to the nucleoside analogue cytarabine (1-B-D-arabinofuranosylcytosine, AraC), two resistant derivatives of the human leukemic line CCRF-CEM were obtained by stepwise selection in different concentrations of AraC. CEM/4ÂAraC cells showed low AraC resistance, whereas CEM/20ÂAraC cells showed high resistance. Both cell lines showed similar patterns of crossresistance to multiple cytotoxic nucleoside analogues, with the exception that CEM/20ÂAraC cells remained sensitive to 5-fluorouridine and 2-deoxy-5-fluorouridine. Both cell lines were sensitive to 5-fluorouracil and to a variety of natural product drugs. Although both CEM/4ÂAraC and CEM/ 20ÂAraC cells displayed reduced intracellular accumulation of [ 3 H]AraC, only CEM/4ÂAraC cells showed reduced uptake of [ 3 H]uridine, which was used to assess nucleoside transport activities. Genes encoding proteins known to be involved in nucleoside transport, efflux, and metabolism were analyzed for the presence of mutations in the two cell lines. In CEM/4ÂAraC cells, independent mutations were identified at each allele of human equilibrative nucleoside transporter 1 (hENT1; SLC29A1), one corresponding to a single-nucleotide change in exon 4, the other being a complex intronic mutation disrupting splicing of exon 13. In contrast to CEM/20ÂAraC cells, CEM/4ÂAraC cells did not bind the hENT1/SLC29A1 ligand nitrobenzylmercaptopurine ribonucleoside and lacked detectable hENT1/SLC29A1 protein. In CEM/20ÂAraC cells, independent intronic mutations impairing splicing of exons 2 and 3 were found at each allele of the deoxycytidine kinase gene. These studies point to at least two distinct mechanisms of AraC resistance in leukemic cells. [Cancer Res 2008;68(7):2349-57]

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Section: Introductionmentioning

confidence: 99%

Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells

et al. 2008

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“…The postremission therapy consisted of 6 courses of idarubicin and cytarabine. 26 Since 2001, patients with APL have been treated with the TPOG-APL-2001 protocol, which was modified from the Programa para el Estudio de la Terape´utica en Hemopatı´a Maligna (PETHEMA) protocol. 27 The non-APL patients were randomized to TPOG-AML-97A protocol 26 or AML-97B protocol, which was modified from Medical Research Council (MRC) AML 10.…”

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confidence: 99%

“…26 Since 2001, patients with APL have been treated with the TPOG-APL-2001 protocol, which was modified from the Programa para el Estudio de la Terape´utica en Hemopatı´a Maligna (PETHEMA) protocol. 27 The non-APL patients were randomized to TPOG-AML-97A protocol 26 or AML-97B protocol, which was modified from Medical Research Council (MRC) AML 10.Cell fractionation, DNA and RNA extraction, and cDNA preparation Mononuclear cells were obtained from bone marrow aspirates at diagnosis and cryopreserved until testing. Genomic DNA (gDNA) and RNA were extracted from freshly frozen cells.…”

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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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“…The treatment results for childhood ALL and AML in Taiwan have improved during the last decade [9,16]. Although infant leukemia is ranked as the most frequent cancer in infants in Taiwan, reports regarding its clinical and biologic features are rare [23].…”

Section: Discussionmentioning

confidence: 99%

“…Infants with AML were treated with TPOG-AML-901 (before 1997) and TPOG-AML-97 protocol (after 1997) [15,16]. These protocols included the use of epidoxorubicin/idarubicin for 3 days and cytarabine for 7 days of induction therapy, followed by several courses of postremission therapy and maintenance therapy.…”

Section: Therapymentioning

confidence: 99%

Clinical features, molecular diagnosis, and treatment outcome of infants with leukemia in Taiwan

Chen

Yang

Hung

et al. 2010

Pediatric Blood & Cancer

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Background. Infant leukemia is rare and quite distinct from other childhood leukemias. Differentiating between leukemia and transient myeloproliferative disorder (TMD) in phenotypically normal infants is sometimes difficult. The clinical features and molecular analyses for the fusion transcripts of mixed lineage leukemia (MLL) gene rearrangement in infant leukemia have not been well documented in the Chinese population. Procedure. Forty-five consecutive infants diagnosed with leukemia between 1995 and 2007 in a tertiary medical center in Taiwan were studied. Acute lymphoblastic leukemia (ALL) was diagnosed in 23 infants, acute myeloid leukemia (AML) in 21 (including TMD in 4), and juvenile myelomonocytic leukemia (JMML) in 1. Results. The median white count at diagnosis was higher in ALL than in AML (154.4 × 10 9 /l vs. 58.3 × 10 9 /l, P = 0.05). Chromosome 11q23/MLL abnormalities were present in 77% of ALL and 31% of AML. The 5-year event-free survival (EFS) in infant ALL and AML showed no difference (18% vs. 12%, respectively). The only independent predictor of an adverse prognosis among infants diagnosed with ALL was high presenting white count ≥ 100 × 10 9 /l (P = 0.05). However, no factor was associated with an adverse outcome for infants with AML. Conclusions. The molecular assessments and prognostic factors of infant leukemia in Taiwan mirror those in developed Western countries. Continued molecular investigations and development of more effective therapies are needed.

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Improved treatment results for childhood acute myeloid leukemia in Taiwan

Cited by 40 publications

References 52 publications

Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells

Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells

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

Clinical features, molecular diagnosis, and treatment outcome of infants with leukemia in Taiwan

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