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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Bibliographic Details
Published in:Nature genetics Vol. 41; no. 11; pp. 1243 - 1246
Main Authors: 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
Language:English
Published: New York Nature Publishing Group US 01.11.2009
Nature Publishing Group
Subjects:
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
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Summary: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.
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/ng.469