Clonal origins of relapse in ETV6-RUNX1 acute lymphoblastic leukemia

Delft, Frederik W. van; Horsley, Sharon W.; Colman, Sue; Anderson, Kristina; Bateman, Caroline M.; Kempski, Helena; Zuna, Jan; Eckert, Cornelia; Saha, Vaskar; Kearney, Lyndal; Ford, Anthony M.; Greaves, Mel

doi:10.1182/blood-2010-10-314674

Cited by 86 publications

(78 citation statements)

References 47 publications

(87 reference statements)

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“…Based on our results and literature (Schindler et al 2009;van Delft et al 2011), we suggest that E/R impairs B cell differentiation through transcriptional reprogramming and renders pre-leukemic cells susceptible to additional genetic hits for an extended period of time. The results pave the way for further characterization of the TF network that mediates commitment to B cell fate and the specific contribution of leukemic TF fusions derailing this process.…”

Section: Discussionsupporting

confidence: 71%

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia

et al. 2016

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Approximately 20%-25% of childhood acute lymphoblastic leukemias carry the ETV6-RUNX1 (E/R) fusion gene, a fusion of two central hematopoietic transcription factors, ETV6 (TEL) and RUNX1 (AML1). Despite its prevalence, the exact genomic targets of E/R have remained elusive. We evaluated gene loci and enhancers targeted by E/R genome-wide in precursor B acute leukemia cells using global run-on sequencing (GRO-seq). We show that expression of the E/R fusion leads to widespread repression of RUNX1 motif-containing enhancers at its target gene loci. Moreover, multiple super-enhancers from the CD19 + /CD20 + -lineage were repressed, implicating a role in impediment of lineage commitment. In effect, the expression of several genes involved in B cell signaling and adhesion was down-regulated, and the repression depended on the wild-type DNA-binding Runt domain of RUNX1. We also identified a number of E/R-regulated annotated and de novo noncoding genes. The results provide a comprehensive genome-wide mapping between E/R-regulated key regulatory elements and genes in precursor B cell leukemia that disrupt normal B lymphopoiesis.

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Section: Discussionsupporting

confidence: 71%

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia

et al. 2016

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“…Support for this notion has been obtained from multiple studies that did SNP array analysis of DNA copy number alterations of matched samples obtained at diagnosis and relapse (25,(46)(47)(48)(49). Genetically identical diagnosis and relapse clones are uncommon (Fig.…”

Section: Clonal Heterogeneity In Leukemiamentioning

confidence: 89%

Advances in the Genetics of High-Risk Childhood B-Progenitor Acute Lymphoblastic Leukemia and Juvenile Myelomonocytic Leukemia: Implications for Therapy

Loh

Mullighan

2012

Clinical Cancer Research

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Hematologic malignancies of childhood comprise the most common childhood cancers. These neoplasms derive from the pathologic clonal expansion of an abnormal cancer-initiating cell and span a diverse spectrum of phenotypes, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS). Expansion of immature lymphoid or myeloid blasts with suppression of normal hematopoiesis is the hallmark of ALL and AML, whereas MPN is associated with proliferation of 1 or more lineages that retain the ability to differentiate, and MDS is characterized by abnormal hematopoiesis and cytopenias. The outcomes for children with the most common childhood cancer, B-progenitor ALL (B-ALL), in general, is quite favorable, in contrast to children affected by myeloid malignancies. The advent of highly sensitive genomic technologies reveals the remarkable genetic complexity of multiple subsets of high-risk B-progenitor ALL, in contrast to a somewhat simpler model of myeloid neoplasms, although a number of recently discovered alterations displayed by both types of malignancies may lead to common therapeutic approaches. This review outlines recent advances in our understanding of the genetic underpinnings of high-risk B-ALL and juvenile myelomonocytic leukemia, an overlap MPN/MDS found exclusively in children, and we also discuss novel therapeutic approaches that are currently being tested in clinical trials. Recent insights into the clonal heterogeneity of leukemic samples and the implications for diagnostic and therapeutic approaches are also discussed. Clin Cancer Res; 18(10); 2754-67. Ó2012 AACR. Acute Lymphoblastic LeukemiaAcute lymphoblastic leukemia (ALL) is the commonest childhood malignancy and, despite progressive improvements in the outcome of therapy, remains the leading cause of cancer-related death in children and young adults (1). ALL is characterized by accumulation of immature lymphoid progenitors in the bone marrow, peripheral blood, and central nervous system and results in death from the consequences of bone marrow failure: anemia, neutropenia and infection, and thrombocytopenia and bleeding. Although these features are common to all patients, ALL represents a remarkably diverse range of subtypes characterized by distinct constellations of gross and submicroscopic genetic alterations, including chromosomal translocations, structural variants, and DNA sequence mutations.Many of these lesions are central events in leukemogenesis, and several are also important determinants of the risk of treatment failure and relapse. General overviews of the genetic basis of ALL may be found in several recent excellent reviews (2-6). This review is part of a series of articles in this issue reviewing new genetic insights and therapeutic opportunities in childhood malignancies (7-11). Here, we briefly review key chromosomal rearrangements in ALL and then focus on several high-risk subtypes, which have hitherto been poorly understood and for which r...

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“…Microarray profiling has shown that relapse samples exhibit striking differences in the patterns of genomic alterations from the matched diagnosis samples (104)(105)(106)(107)(108), with the majority of relapse samples exhibiting the loss of CNAs present at diagnosis and the acquisition of new genetic alterations. Importantly, most paired diagnosis-relapse samples share a common clonal origin.…”

Section: Genetics Of Relapse In Allmentioning

confidence: 99%

Molecular genetics of B-precursor acute lymphoblastic leukemia

2012

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B-precursor acute lymphoblastic leukemia (B-ALL) is the most common childhood tumor and the leading cause of cancer-related death in children and young adults. The majority of B-ALL cases are aneuploid or harbor recurring structural chromosomal rearrangements that are important initiating events in leukemogenesis but are insufficient to explain the biology and heterogeneity of disease. Recent studies have used microarrays and sequencing to comprehensively identify all somatic genetic alterations in acute lymphoblastic leukemia (ALL). These studies have identified cryptic or submicroscopic genetic alterations that define new ALL subtypes, cooperate with known chromosomal rearrangements, and influence prognosis. This article reviews these advances, discusses results from ongoing second-generation sequencing studies of ALL, and highlights challenges and opportunities for future genetic profiling approaches.

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Clonal origins of relapse in ETV6-RUNX1 acute lymphoblastic leukemia

Abstract: B-cell precursor childhood acute lymphoblastic leukemia with ETV6-RUNX1 (TEL-AML1

Cited by 86 publications

References 47 publications

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia

Advances in the Genetics of High-Risk Childhood B-Progenitor Acute Lymphoblastic Leukemia and Juvenile Myelomonocytic Leukemia: Implications for Therapy

Molecular genetics of B-precursor acute lymphoblastic leukemia

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