Yao Zou

Identification of functional cooperative mutations of SETD2 in human acute leukemia

Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene–rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.

Long-term outcome after immunosuppressive therapy with horse or rabbit antithymocyte globulin and cyclosporine for severe aplastic anemia in children

Some prospective studies showed that rabbit antithymocyte globulin was inferior to horse antithymocyte globulin as first-line therapy for patients with severe aplastic anemia. We retrospectively analyzed the clinical outcome of 455 children with severe aplastic anemia who received horse antithymocyte globulin (n=297) or rabbit antithymocyte globulin (n=158) combined with cyclosporine as first-line therapy between 1992 and 2010. The response rates were comparable between the horse and rabbit antithymocyte globulin groups at 3 months [46% (136/294) versus 42% (66/153), P=0.55] and 6 months [60% (178/292) versus 55% (87/143), P=1.0]. Using multivariate analysis, differences in antithymocyte globulin preparations were not associated with response rates. However, 2-year and 10-year overall survival rates in the horse antithymocyte globulin group were significantly better than those in the rabbit antithymocyte globulin group (2-year overall survival: 96% versus 87%, 10-year overall survival: 92% versus 84%, P=0.004). On the basis of multivariate analysis, use of rabbit antithymocyte globulin was a significant adverse factor for overall survival (hazard ratio = 3.56, 95% confidence interval, 1.53 – 8.28, P=0.003). Rabbit antithymocyte globulin caused more profound immunosuppression, which might be responsible for the higher incidence of severe infections. Considering that there are no studies showing the superiority of rabbit antithymocyte globulin over horse antithymocyte globulin, horse antithymocyte globulin should be recommended as a first-line therapy. However, our results justify the use of rabbit antithymocyte globulin as first-line therapy if horse antithymocyte globulin is not available.

Cyclin D1 gene polymorphism and susceptibility to childhood acute lymphoblastic leukemia in a Chinese population.

Cyclin D1 is a key protein involved in cell cycle regulation. A common A870G single nucleotide polymorphism in exon 4 of the cyclin D1 gene (CCND1) has an effect on the transcription of 2 different cyclin D1 messenger RNAs. Correlation between genetic polymorphism of A870G of CCND1 and clinical outcome among patients with acute lymphoblastic leukemia (ALL) has been reported. However, the effect on ALL occurrence remains unclear. To examine the genotypic frequency of CCND1 polymorphism, we performed a case-control study in a Chinese population of 183 children with ALL and 190 healthy controls. The genetic frequency of CCND1 had a significant overall correlation in patients and controls. The AA genotype of CCND1 showed a tendency to increase ALL risk 3.2898-fold compared with the AG + GG genotype (P = .0207). Stratification of patients according to cell type, risk level, and chemotherapeutic response showed significance for the AA genotype in T-cell ALL, ALL with high risk, and no complete remission (P = .047, P = .011, and P = .007, respectively). No gene dosage effect was observed in this study. The results of the present study suggested that CCND1 genetic polymorphism may be related to the occurrence of ALL in a population of Chinese children.

Retrospective analysis of 65 Chinese children with acute promyelocytic leukemia: A single center experience

There are very limited data reported about childhood acute promyelocytic leukemia (APL), especially with arsenic trioxide (As2O3) treatment. We review the clinical course and treatment outcome of 65 children APL.

Monitoring the AML1/ETO fusion transcript to predict outcome in childhood acute myeloid leukemia

To determine the prognostic significance of the detection of the minimal residual disease (MRD) in children with AML1/ETO AML, we compared the results of reverse‐transcription polymerase chain reaction (RT‐PCR) and quantitative reverse‐transcription polymerase chain reaction (RQ‐PCR).

Transient pancytopenia preceding T lineage acute lymphoblastic leukemia.

Transient pancytopenia preceding acute lymphoblastic leukemia (pre-ALL) is a rare occurrence usually affecting children with subsequent development of B lineage ALL. We report a case of pre-ALL characterized by a T cell immunophenotype and abnormal karyotype t (11; 14) (q10; q10). The patient achieved a transient complete remission after initial therapy, but relapsed within a few months and died of leukemic encephalopathy. To the best of our knowledge, this is the first report of T lineage pre-ALL.

The role of standard-dose cytarabine in children with acute promyelocytic leukemia: a single-center experience.

Background There are very limited data reported about the role of cytarabine (Ara-C) in childhood acute promyelocytic leukemia (APL). We review the clinical course and treatment outcome of APL and explore the role of standard-dose Ara-C for children. Procedure Between January 1999 and December 2008, 36 children (<14 y) with newly diagnosed APL were included. Results The overall complete remission rate was 97.2% (35/36). Two patients were lost to follow-up after induction. Two groups of patients were identified according to different consolidation chemotherapy regimens. Seventeen patients were given polychemotherapy in combination with standard-dose Ara-C (group I), 16 patients were given daunorubicin alone (group II). Although the 5-year estimate of disease-free survival between groups I and II had no statistically significant difference (P=0.614), there was a 12% higher disease-free survival rate for group I. Conclusion Standard-dose Ara-C might play some role in the consolidation treatment of children suffering from APL.

Whole exome sequencing identifies novel mutations of epigenetic regulators in chemorefractory pediatric acute myeloid leukemia

Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.

FLT3 pathway is a potential therapeutic target for PRC2 mutated T cell acute lymphoblastic leukemia

TO THE EDITOR: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, and T-cell ALL (T-ALL) accounts for approximately 15% of cases of childhood ALL.[1][1],[2][2] Early T-cell precursor ALL (ETP-ALL) is a recently recognized subtype of T-ALL.[3][3],[4][4] Hallmarks of T-ALL

Outcome of children with newly diagnosed acute lymphoblastic leukemia treated with CCLG-ALL 2008: The first nation-wide prospective multicenter study in China

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. The trial Chinese Children Leukemia Group (CCLG)‐ALL 2008 was a prospective clinical trial designed to improve treatment outcome of childhood ALL through the first nation‐wide collaborative study in China. Totally 2231 patients were recruited from ten tertiary hospitals in eight cities. The patients were stratified according to clinical‐biological characteristics and early treatment response. Standard risk (SR) and intermediate risk (IR) groups were treated with a modified BFM based protocol, and there was 25%‐50% dose reduction during intensification phases in the SR group. Patients in high risk (HR) group received a more intensive maintenance treatment. Minimal residual disease (MRD) monitoring with treatment adjustment was performed in two hospitals (the MRD group). Complete remission (CR) was achieved in 2100 patients (94.1%). At five years, the estimate for overall survival (OS) and event‐free survival (EFS) of the whole group was 85.3% and 79.9%, respectively. The cumulative incidence of relapse (CIR) was 15.3% at five years. The OS, EFS and CIR for the SR group were 91.5%, 87.9%, and 9.7%, respectively. The outcome of the MRD group is better than the non‐MRD group (5y‐EFS: 82.4% vs 78.3%, P = .038; 5y‐CIR: 10.7% vs 18.0%, P < .001). Our results demonstrated that the large‐scale multicenter trial for pediatric ALL was feasible in China. Dose reduction in the SR group could achieve high EFS. MRD‐based risk stratification might improve the treatment outcome for childhood ALL.