Rearrangement of CRLF2 in B-progenitor– and Down syndrome–associated acute lymphoblastic leukemia

Charles Mullighan and colleagues report a recurrent rearrangement of CRLF2 in B-progenitor and Down syndrome-associated acute lymphoblastic leukemia. Their genetic and functional evidence indicates that CRLF2 cooperates with activated JAK2 to promote leukemogenesis. Aneuploidy and translocations are...

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Veröffentlicht in:	Nature genetics Jg. 41; H. 11; S. 1243 - 1246
Hauptverfasser:	Mullighan, Charles G, Collins-Underwood, J Racquel, Phillips, Letha A A, Loudin, Michael G, Liu, Wei, Zhang, Jinghui, Ma, Jing, Coustan-Smith, Elaine, Harvey, Richard C, Willman, Cheryl L, Mikhail, Fady M, Meyer, Julia, Carroll, Andrew J, Williams, Richard T, Cheng, Jinjun, Heerema, Nyla A, Basso, Giuseppe, Pession, Andrea, Pui, Ching-Hon, Raimondi, Susana C, Hunger, Stephen P, Downing, James R, Carroll, William L, Rabin, Karen R
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.11.2009 Nature Publishing Group
Schlagworte:	Acute lymphocytic leukemia Agriculture Amino Acid Sequence Animal Genetics and Genomics Animals Base Sequence Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Cancer Research Cell cycle Cell Line Chromosome aberrations Chromosome Deletion Chromosomes Down syndrome Down Syndrome - complications Down Syndrome - genetics Fundamental and applied biological sciences. Psychology Gene Function Gene mutations Gene Rearrangement Genetic aspects Genetics Genetics of eukaryotes. Biological and molecular evolution Genomics Health aspects Hematologic and hematopoietic diseases Hospitals Human Genetics Humans Janus Kinase 2 - genetics Janus Kinase 2 - metabolism Kinases letter Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical genetics Medical research Medical sciences Mice Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - complications Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Receptors, Cytokine - chemistry Receptors, Cytokine - genetics Receptors, Cytokine - metabolism Receptors, Purinergic P2 - genetics Receptors, Purinergic P2 - metabolism Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Risk factors Studies United States Chromosomal aberration Trisomy Lymphoproliferative syndrome Acute leukemia Aneuploidy Malignant hemopathy Down syndrome Acute lymphocytic leukemia Cancer
ISSN:	1061-4036, 1546-1718, 1546-1718
Online-Zugang:	Volltext
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Zusammenfassung:	Charles Mullighan and colleagues report a recurrent rearrangement of CRLF2 in B-progenitor and Down syndrome-associated acute lymphoblastic leukemia. Their genetic and functional evidence indicates that CRLF2 cooperates with activated JAK2 to promote leukemogenesis. Aneuploidy and translocations are hallmarks of B-progenitor acute lymphoblastic leukemia (ALL), but many individuals with this cancer lack recurring chromosomal alterations. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2 . We identified the P2RY8-CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8-CRLF2 together with mutated mouse Jak2 resulted in constitutive Jak-Stat activation and cytokine-independent growth of Ba/F3 cells overexpressing interleukin-7 receptor alpha. Our findings indicate that these two genetic lesions together contribute to leukemogenesis in B-progenitor ALL.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.469