Precision medicine approaches may be the future for CRLF2 rearranged Down Syndrome Acute Lymphoblastic Leukaemia patients.

Elyse C Page, Susan L Heatley, David T Yeung, Paul Q Thomas, Deborah L White

Journal: Cancer letters 2019;432():69-74

PMID: 29879498

Full Text on Elsevier Science View on PubMed

Abstract

Breakthrough studies over the past decade have uncovered unique gene fusions implicated in acute lymphoblastic leukaemia (ALL). The critical gene, cytokine receptor-like factor 2 (CRLF2), is rearranged in 5-16% of B-ALL, comprising 50% of Philadelphia-like ALL and cooperates with genomic lesions in the Jak, Mapk and Ras signalling pathways. Children with Down Syndrome (DS) have a predisposition to developing CRLF2 rearranged-ALL which is observed in 60% of DS-ALL patients. These patients experience a poor survival outcome. Mutations of genes involved in epigenetic regulation are more prevalent in DS-ALL patients than non-DS ALL patients, highlighting the potential for alternative treatment strategies. DS-ALL patients also suffer greater treatment-related toxicity from current ALL treatment regimens compared to non-DS-ALL patients. An increased gene dosage of critical genes on chromosome 21 which have roles in purine synthesis and folate transport may contribute. As the genomic landscape of DS-ALL patients is different to non-DS-ALL patients, targeted therapies for individual lesions may improve outcomes. Therapeutically targeting each rearrangement with targeted or combination therapy that will perturb the transforming signalling pathways will likely improve the poor survival rates of this subset of patients.

Address: Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia. Electronic address: [email protected].; Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia; Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG), Australia; The Kids' Cancer Project, Australia. Electronic address: [email protected].; Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia; Haematology Department, SA Pathology, Australia. Electronic address: [email protected].; Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia. Electronic address: [email protected].; Cancer Theme, South Australian Health & Medical Research Institute, Adelaide, SA, Australia; Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia; Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG), Australia; The Kids' Cancer Project, Australia; Australian Genomic Health Alliance (AGHA), Australia; Discipline of Paediatrics, University of Adelaide, Adelaide, SA, Australia. Electronic address: [email protected].

DOI: 10.1016/j.canlet.2018.05.045