Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

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...

Full description

Saved in:

Bibliographic Details
Published in:	Leukemia Vol. 31; no. 7; pp. 1491 - 1501
Main Authors:	Vesely, C, Frech, C, Eckert, C, Cario, G, Mecklenbräuker, A, zur Stadt, U, Nebral, K, Kraler, F, Fischer, S, Attarbaschi, A, Schuster, M, Bock, C, Cavé, H, von Stackelberg, A, Schrappe, M, Horstmann, M A, Mann, G, Haas, O A, Panzer-Grümayer, R
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-07-2017 Nature Publishing Group
Subjects:	38/39 45/23 45/47 631/208/69 631/337/572 631/67/1990/283/2125 692/699/67/2332 Aberration Acute lymphoblastic leukemia Acute lymphocytic leukemia Adhesion Adolescent Analysis Bone marrow Cancer Research Care and treatment Cell cycle Cell self-renewal Child Child, Preschool Children Critical Care Medicine Deregulation Diagnosis Differentiation Drug resistance Gene Dosage Gene Fusion Gene sequencing Genes, Tumor Suppressor Genomics Hematology Homing Humans Hypoxia Ikaros protein Ikaros Transcription Factor - genetics Ikaros Transcription Factor - physiology Infant Intensive Internal Medicine Janus Kinases - physiology Leukemia Lymphatic leukemia Medicine Medicine & Public Health Mutation Oncology Original original-article Polymorphism, Single Nucleotide Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Receptors, Cytokine - genetics Receptors, Purinergic P2Y - genetics Ribonucleic acid RNA STAT Transcription Factors - physiology Stem cells Therapeutic applications Transcription Transcription, Genetic
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	0887-6924 1476-5551
DOI:	10.1038/leu.2016.365