title: Characterisation of the genomic landscape of CRLF2-rearranged acute lymphoblastic leukemia.
abstract: Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We aimed to determine the clinical and genetic landscape of those with IGH-CRLF2 or P2RY8-CRLF2 (CRLF2-r) using multiple genomic approaches. Clinical and demographic features of CRLF2-r patients were characteristic of B-ALL. Patients with IGH-CRLF2 were older (14 y vs. 4 y, P < .001), while the incidence of CRLF2-r among Down syndrome patients was high (50/161, 31%). CRLF2-r co-occurred with primary chromosomal rearrangements but the majority (111/161, 69%) had B-other ALL. Copy number alteration (CNA) profiles were similar to B-other ALL, although CRLF2-r patients harbored higher frequencies of IKZF1 (60/138, 43% vs. 77/1351, 24%) and BTG1 deletions (20/138, 15% vs. 3/1351, 1%). There were significant differences in CNA profiles between IGH-CRLF2 and P2RY8-CRLF2 patients: IKZF1 (25/35, 71% vs. 36/108, 33%, P < .001), BTG1 (11/35, 31% vs. 10/108, 9%, P =.004), and ADD3 deletions (9/19, 47% vs. 5/38, 13%, P =.008). A novel gene fusion, USP9X-DDX3X, was discovered in 10/54 (19%) of patients. Pathway analysis of the mutational profile revealed novel involvement for focal adhesion. Although the functional relevance of many of these abnormalities are unknown, they likely activate additional pathways, which may represent novel therapeutic targets.
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Russell
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Jones
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Amir
authors.initials: A
authors.lastname: Enshaei
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tonin
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Sarra L
authors.initials: SL
authors.lastname: Ryan
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Jeyanthy
authors.initials: J
authors.lastname: Eswaran
authors.affiliation: Bioinformatics Support Unit, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Sirintra
authors.initials: S
authors.lastname: Nakjang
authors.affiliation: Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, USA.|Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Jose M C
authors.initials: JM
authors.lastname: Tubio
authors.affiliation: Research Department of Haemaoloty, UCL Cancer Institute, London, UK.
authors.forename: Adele K
authors.initials: AK
authors.lastname: Fielding
authors.affiliation: Department of Haematology, Sheffield Children's Hospital, Sheffield, UK.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Christine J
authors.identifier: 0000-0002-0526-6794
authors.initials: CJ
authors.lastname: Harrison
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D015321:Gene Rearrangement; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D018121:Receptors, Cytokine / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C498762:CRLF2 protein, human; D015514:Oncogene Proteins, Fusion; D018121:Receptors, Cytokine