Children's Oncology Group blueprint for research: Acute lymphoblastic leukemia

Raetz, Elizabeth A.; Bhojwani, Deepa; Devidas, Meenakshi; Gore, Lia; Rabin, Karen R.; Tasian, Sarah K.; Teachey, David T.; Loh, Mignon L.

doi:10.1002/pbc.30585

Cited by 9 publications

(3 citation statements)

References 88 publications

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“…In the best-case scenario, somatic mutations acquired in these patients might be druggable. Salient examples include BCR::ABL1 and ABL class fusions as targetable by imatinib or dasatinib, CRLF2, JAK2, and EPOR rearrangements as targetable by ruxolitinib, and KMT2A rearrangements as targetable by menin inhibitors [reviewed in (37)]. However, most pediatric leukemias, especially B-ALL, are mutationally "quiet", limiting the utility of gene panels as currently implemented.…”

Section: Discussionmentioning

confidence: 99%

An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia

Torres-Diz,

Reglero,

Falkenstein

et al. 2023

Preprint

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Relapse-specific mutations do not account for all chemotherapy failures in patients with B-cell acute lymphoblastic leukemia (B-ALL). By mining RNA-seq datasets of paired diagnostic/relapse pediatric B-ALL samples, we discovered pervasive aberrant splicing (AS) patterns linked with relapse. They affected drivers of resistance to glucocorticoids, anti-folates, and thiopurines. Most splicing variations represent exon skipping, "poison" exon inclusion, and intron retention, phenocopying well-documented loss-of-function mutations. In addition, relapse-associated AS of NT5C2 mRNA yields an isoform with a cryptic 24-nt in-frame exon 6a. Inclusion of the extra 8 amino acids into this enzyme results in elevated nucleosidase activity, a known consequence of gain-of-function mutations in NT5C2 and a common determinant of 6-mercaptopurine resistance. Furthermore, in B-ALL cells NT5C2ex6a and the R238W hotspot variant confers comparable levels of resistance to 6-mercaptopurine in vitro and in vivo. These results support a role for alternative splicing as a prevalent mechanism driving chemotherapy resistance in relapsed B-ALL.

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Section: Discussionmentioning

confidence: 99%

An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia

Torres-Diz,

Reglero,

Falkenstein

et al. 2023

Preprint

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“…BCP-ALL has peaks of incidence in childhood and in older adults. It is the most common childhood malignancy but in recent years has become largely treatable, with survival in children of around 85-92% (79,80). Older adults still have a much less favorable prognosis (81,82).…”

Section: The Human Bone Marrow Is a Nursery For Normal And Abnormal P...mentioning

confidence: 99%

Glycosylation as regulator of human B-cell leukaemias in bone marrow

Heisterkamp

2023

Front. Hematol.

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Leukemic B-cells are lodged in the bone marrow [BM], a complex organ composed of many cell types and extracellular matrix. Determining how the reciprocal interactions between these components are regulated is critical to our understanding of the factors that allow leukemia cells to survive, multiply and withstand treatment. All cells in the bone marrow are surrounded by a glycocalyx, a glycan-rich layer of high complexity, which regulates such cell-cell and cell-matrix interactions. However, the structure and function of the glycan components of the biomolecules that constitute this layer have not been explored in much detail. Gaps are difficult to fill due to technical limitations as well as the fact that the composition of the BM in health, disease and aging is not static. This also applies to B-lineage malignancies that develop or persist in BM such as B-cell precursor acute lymphoblastic leukemia and Multiple Myeloma, and the effects of their treatment. In contrast, the proteomes and transcriptomes of different human bone marrow cells have been studied more extensively. A combination of technologies now increasingly allows correlations to be made between the expression of glycosyltransferases and glycan structures in cell lines, which could be extrapolated to RNAseq data from primary cells. Glycopeptide analysis will also be invaluable in providing details of specific glycan occupancy on glycoproteins, even if only as a snapshot in time. Functional studies on CD19, CD138/SDC1 and BCMA/TNFRSF17 have already demonstrated the importance of their glycosylation. Additional studies using such approaches are likely to find many more other instances in which malignant B-cell homeostasis is regulated by glycosylation, and lead to the identification of new targets to treat B-cell malignancies.

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“…are cured following contemporary therapies. 4 Survival remains very poor for children with high-grade glioma, diffuse midline glioma and metastatic sarcoma. 5,6 Improvements in survival over past decades can be attributed primarily to advances in treatment, including intensity of chemotherapy and supportive care, and enrolment in clinical trials for most patients.…”

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confidence: 99%

Proteomic insights into paediatric cancer: Unravelling molecular signatures and therapeutic opportunities

Padhye,

Nawaz,

Hains

et al. 2024

Pediatric Blood & Cancer

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Survival rates in some paediatric cancers have improved greatly over recent decades, in part due to the identification of diagnostic, prognostic and predictive molecular signatures, and the development of risk‐directed therapies. However, other paediatric cancers have proved difficult to treat, and there is an urgent need to identify novel biomarkers that reveal therapeutic opportunities. The proteome is the total set of expressed proteins present in a cell or tissue at a point in time, and is vastly more dynamic than the genome. Proteomics holds significant promise for cancer research, as proteins are ultimately responsible for cellular phenotype and are the target of most anticancer drugs. Here, we review the discoveries, opportunities and challenges of proteomic analyses in paediatric cancer, with a focus on mass spectrometry (MS)‐based approaches. Accelerating incorporation of proteomics into paediatric precision medicine has the potential to improve survival and quality of life for children with cancer.

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Children's Oncology Group blueprint for research: Acute lymphoblastic leukemia

Cited by 9 publications

References 88 publications

An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia

An Alternatively Spliced Gain-of-Function NT5C2 Isoform Contributes to Chemoresistance in Acute Lymphoblastic Leukemia

Glycosylation as regulator of human B-cell leukaemias in bone marrow

Proteomic insights into paediatric cancer: Unravelling molecular signatures and therapeutic opportunities

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