Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J et al.. Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood 115: 1006-1017

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Blood (Impact Factor: 10.45). 11/2009; 115(5):1006-17. DOI: 10.1182/blood-2009-08-235408
Source: PubMed


We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was identified. Consistent with our previous research, mutations in R683 of JAK2 were identified in 10 specimens (19% of the patients) and, interestingly, all 10 had high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3 pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell lymphocytic genomic instability. Thus, DS confers increased risk for genetically highly diverse ALLs with frequent overexpression of CRLF2, associated with activating mutations in the receptor itself or in JAK2. Our data also suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways.

Download full-text


Available from: Lisa J Russell
  • Source
    • "Mutation of JAK2 is observed in several hematological disorders including ET [8,9,10,11], Polycythemia Vera [8,9,10,11], Primary Myelofibrosis [8,9,10,11] and Acute Lymphoid Leukemia (ALL) [25,26] as well as chromosomal translocations involving the fusion partners TEL [27,28,29], BCR [30], PCM1 [31,32,33], PAX5 [34], SEC 31A [35] and SSBP2 [36]. The JAK2 signaling network also participates in disease mediated by MPL mutations in ET and CRLF2 mutations in T cell ALL [37,38,39,40]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Utilizing ENU mutagenesis, we identified a mutant mouse with elevated platelets. Genetic mapping localized the mutation to an interval on chromosome 19 that encodes the Jak2 tyrosine kinase. We identified a A3056T mutation resulting in a premature stop codon within exon 19 of Jak2 (Jak2 (K915X) ), resulting in a protein truncation and functionally inactive enzyme. This novel platelet phenotype was also observed in mice bearing a hemizygous targeted disruption of the Jak2 locus (Jak2 (+/-) ). Timed pregnancy experiments revealed that Jak2 (K915X/K915X) and Jak2 (-/-) displayed embryonic lethality; however, Jak2 (K915X/K915X) embryos were viable an additional two days compared to Jak2 (-/-) embryos. Our data suggest that perturbing JAK2 activation may have unexpected consequences in elevation of platelet number and correspondingly, important implications for treatment of hematological disorders with constitutive Jak2 activity.
    Full-text · Article · Sep 2013 · PLoS ONE
  • Source
    • "Patients with trisomy 21 are also at increased risk of developing ALL. Recently, JAK2 mutations as well high expression levels of the cytokine receptor CRLF2 have been found in 19% and 66% of patients with Down syndrome and ALL, respectively [Mullighan et al. 2009; Hertzberg et al. 2010]. Overexpression of CRLF2 is associated with genomic lesions of CRLF2, most notably in people with Down's syndrome, of a PAR1 deletion that fuses the P2RY8 gene located on the pseudo autosomal regions of the sex chromosomes with the CRFL2 gene. "
    [Show abstract] [Hide abstract]
    ABSTRACT: While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia.
    Full-text · Article · Aug 2013
  • Source
    • "Nearly fifteen years later, the Mano laboratory used essentially the same protocol to identify the EML4-ALK fusion from a lung cancer sample [7]. We previously discovered a mutant allele of the CRLF2 cytokine receptor by screening cDNA libraries generated from primary acute lymphoblastic leukemias (ALL), which multiple groups concurrently identified as an important oncogene in poor-risk ALL [8], [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is a pressing need for methods to define the functional relevance of genetic alterations identified by next-generation sequencing of cancer specimens. We developed new approaches to efficiently construct full-length cDNA libraries from small amounts of total RNA, screen for transforming and resistance phenotypes, and deconvolute by next-generation sequencing. Using this platform, we screened a panel of cDNA libraries from primary specimens and cell lines in cytokine-dependent murine Ba/F3 cells. We demonstrate that cDNA library-based screening can efficiently identify DNA and RNA alterations that confer either cytokine-independent proliferation or resistance to targeted inhibitors, including RNA alterations and intergenic fusions. Using barcoded next-generation sequencing, we simultaneously deconvoluted cytokine-independent clones recovered after transduction of 21 cDNA libraries. This approach identified multiple gain-of-function alleles, including KRAS G12D, NRAS Q61K and an activating splice variant of ERBB2. This approach has broad applicability for identifying transcripts that confer proliferation, resistance and other phenotypes in vitro and potentially in vivo.
    Preview · Article · Nov 2012 · PLoS ONE
Show more