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.

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    • "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]. "
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    PLoS ONE 09/2013; 8(9):e75472. DOI:10.1371/journal.pone.0075472 · 3.23 Impact Factor
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    • "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. "
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    08/2013; 4(4):270-90. DOI:10.1177/2040620713498161
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    • "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]. "
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