title: Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia.
abstract: Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1's critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.
authors.affiliation: Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Vesely
authors.affiliation: Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Frech
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Department of Pediatrics, Medical University of Schleswig Holstein, Kiel, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Cario
authors.affiliation: Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Mecklenbräuker
authors.affiliation: Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Zur Stadt
authors.affiliation: Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Nebral
authors.affiliation: Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Kraler
authors.affiliation: Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Fischer
authors.affiliation: St Anna Kinderspital, Medical University Vienna, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Attarbaschi
authors.affiliation: Research Center for Molecular Medicine (CeMM), Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Schuster
authors.affiliation: Research Center for Molecular Medicine (CeMM), Vienna, Austria.
authors.forename: C
authors.identifier: 0000-0001-6091-3088
authors.initials: C
authors.lastname: Bock
authors.affiliation: UFR de Médecine Paris-Diderot, INSERM UMR_S1131-Institute Universitaire d'hématologie, Département de Génétique-UF de Génétique Moléculaire, Hôpital Robert Debré, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: von Stackelberg
authors.affiliation: Department of Pediatrics, Medical University of Schleswig Holstein, Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Horstmann
authors.affiliation: St Anna Kinderspital, Medical University Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Mann
authors.affiliation: Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.|St Anna Kinderspital, Medical University Vienna, Vienna, Austria.
authors.forename: O A
authors.initials: OA
authors.lastname: Haas
authors.affiliation: Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Panzer-Grümayer
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D018628:Gene Dosage; D050939:Gene Fusion; D016147:Genes, Tumor Suppressor; D023281:Genomics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000502:physiology; D007223:Infant; D053612:Janus Kinases / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D018121:Receptors, Cytokine / Q000235:genetics*; D058470:Receptors, Purinergic P2Y / Q000235:genetics*; D050791:STAT Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: C498762:CRLF2 protein, human; C497239:IKZF1 protein, human; C578279:P2RY8 protein, human; D018121:Receptors, Cytokine; D058470:Receptors, Purinergic P2Y; D050791:STAT Transcription Factors; D051740:Ikaros Transcription Factor; D053612:Janus Kinases