Journal Article

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

Harvey, Richard C, Raimondi, Susana C, Basso, Giuseppe, Downing, James R, Liu, Wei, Cheng, Jinjun, Willman, Cheryl L, Heerema, Nyla A, Williams, Richard T, Collins-Underwood, J Racquel, Meyer, Julia, Pui, Ching-Hon, Carroll, Andrew J, Rabin, Karen R, Phillips, Letha A A, Zhang, Jinghui, Coustan-Smith, Elaine, Ma, Jing, Pession, Andrea, Hunger, Stephen P, Loudin, Michael G, Mikhail, Fady M, Carroll, William L, Mullighan, Charles G

2009

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 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