Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • Remarkable progress has been made in the treatment of

    2018-11-09

    Remarkable progress has been made in the treatment of ALL. Currently, the five-year overall survival rates exceed 85% in pediatric patients in developed countries (Pui et al., 2015), but remain less than 45% in adults (Jabbour et al., 2015; Bassan and Hoelzer, 2011).The poor outcome in adults has been attributed in part to a high frequency of unfavorable genetic subtypes of ALL, pre-existing co-morbidities, and poor tolerance of intensive treatment. In our previous report on large B-ALL cohorts in China, the outcome of both adult and pediatric patients seemed less favorable than that of the best centers in Western countries (Mi et al., 2012). The higher frequency of unfavorable prognostic factors such as BCR-ABL1 and the lower frequency of favorable factors such as ETV6-RUNX1 and hyperdiploidy in Chinese pediatric ALL could contribute to this difference (Chen et al., 2012). However, within the same genetic subtypes of ALL, the leukemic W 54011 of adult patients are more resistant to treatment than those of pediatric patients. For example, cures can be achieved with intensive chemotherapy and an ABL tyrosine kinase inhibitor in up to 70% of children with Philadelphia chromosome-positive ALL with BCR-ABL1 fusion (Chalandon et al., 2015), but in less than 50% of adults even with the addition of transplantation (Chalandon et al., 2015; Jabbour et al., 2015). In a recent study of MLL-rearranged B-ALL, older children had more somatic mutations and had a higher frequency of mutated epigenetic regulators than did infants (Andersson et al., 2015), suggesting important differences in the development and prognosis of leukemia between infants and older children. Thus, we undertook a detailed analysis of B-ALL leukemic cell genomics in adults and children to identify genetic abnormalities in a systematic way and to discover alterations that might explain the inferior prognosis of adult B-ALL and to identify potential therapeutic targets for this high-risk cancer.
    Methods
    Results
    Discussion Of note, MEF2D and ZNF384 fusions were highly recurrent affecting 6.7% and 7.3% of adults, 3.4% and 3.9% of pediatric patients, respectively. Leukemia cases with these two fusions comprised distinct gene expression subgroups (G1 and G5), suggesting that the fusions are oncogenic drivers. Indeed, functional studies confirmed that MEF2D-BCL9, MEF2D-HNRNPUL1 and EP300-ZNF384 fusion genes profoundly disrupted B-cell development in vivo and in vitro. Interestingly, MEF2D fusions up-regulated HDAC9, a class II histone deacetylase, which in turn could cooperate with the fusion transcription factors in the repression of genes essential for B-lineage differentiation (RAG1). Moreover, EP300-ZNF384 fusion alone rapidly gave rise to overt acute leukemia. In our series, EP300-ZNF384 fusion conferred an intermediate prognosis and the gene set enrichment analysis showed significant upregulation of JAK-STAT pathway, suggestive of a potential benefit from treatment with inhibitors of this pathway. By contrast, MEF2D fusions appeared to be associated with a poor prognosis in both adults and children. It may be worthwhile to test histone deacetylase inhibitors in patients with this genotype. Moreover, we discovered a close association between ERG deletion and DUX4 overexpression in G4 subgroup, and future therapies may benefit from a deeper understanding of this cooperative mechanism of the two genetic defects. While analyzing recurrent sequence abnormalities in adult and pediatric B-ALL groups, we found that adult patients had more gene mutations, especially IKZF1, MLL2, and JAK3, but fewer alterations of PTPN11 than did pediatric patients. A number of sequence mutations could cooperate with gene fusions or aberrant expression patterns in disease mechanisms and could exert effect on distinct clinical outcomes between different age groups. For example, the strong association of IKZF1 alteration with Philadelphia chromosome-positive and Philadelphia chromosome-like B-ALL and PTPN11 mutation with hyperdiploid B-ALL suggests that the enrichment for IKZF1 in adults, and PTPN11 in children, is associated with biases in leukemia subtype distribution between the two age groups. On the other hand, our findings of more mutations within each gene expression cluster subgroup, and the enrichment of genetic alterations affecting B-cell development and epigenetic modifier genes in adult B-ALL as compared to pediatric patients in several subgroups, suggest increased complexity of pathway involvements and different target cells for malignant transformation with increasing age, which may partly, albeit not fully, explain the dismal prognosis in adults with B-ALL. Recent studies of clonal evolution of pediatric (Ma et al., 2015; Mullighan et al., 2011) and adult (Xiao et al., 2016) ALL found enrichment of mutations in epigenetic regulators from diagnosis to relapse. It is thus possible that profound chromatin changes owing to more frequent epigenetic modifier abnormalities in adult B-ALL cells confer greater drug-resistance.