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Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia
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Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia
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Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia
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Journal Article
Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia
2017
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 45/23
/ 45/47
/ Acute lymphoblastic leukemia
/ Adhesion
/ Analysis
/ Child
/ Children
/ Genomics
/ Homing
/ Humans
/ Hypoxia
/ Ikaros Transcription Factor - genetics
/ Ikaros Transcription Factor - physiology
/ Infant
/ Leukemia
/ Medicine
/ Mutation
/ Oncology
/ Original
/ Polymorphism, Single Nucleotide
/ Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
/ Receptors, Cytokine - genetics
/ Receptors, Purinergic P2Y - genetics
/ RNA
