Linked Life Data

20841423

Source:http://linkedlifedata.com/resource/pubmed/id/20841423

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
39
pubmed:dateCreated
2010-9-30
pubmed:databankReference
pubmed:abstractText
Here, we report that primary leukemic cells from infants with newly diagnosed B-precursor leukemia express a truncated and functionally defective CD22 coreceptor protein that is unable to transmit apoptotic signals because it lacks most of the intracellular domain, including the key regulatory signal transduction elements and all of the cytoplasmic tyrosine residues. Expression of this structurally and functionally abnormal CD22 protein is associated with a very aggressive in vivo growth of patients' primary leukemia cells causing disseminated overt leukemia in SCID mice. The abnormal CD22 coreceptor is encoded by a profoundly aberrant mRNA arising from a splicing defect that causes the deletion of exon 12 (c.2208-c.2327) (CD22?E12) and results in a truncating frameshift mutation. The splicing defect is associated with multiple homozygous mutations within a 132-bp segment of the intronic sequence between exons 12 and 13. These mutations cause marked changes in the predicted secondary structures of the mutant CD22 pre-mRNA sequences that affect the target motifs for the splicing factors hnRNP-L, PTB, and PCBP that are up-regulated in infant leukemia cells. Forced expression of the mutant CD22?E12 protein in transgenic mice perturbs B-cell development, as evidenced by B-precursor/B-cell hyperplasia, and corrupts the regulation of gene expression, causing reduced expression levels of several genes with a tumor suppressor function. We further show that CD22?E12-associated unique gene expression signature is a discriminating feature of newly diagnosed infant leukemia patients. These striking findings implicate CD22?E12 as a previously undescribed pathogenic mechanism in human B-precursor leukemia.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1091-6490
pubmed:author
pubmed:issnType
Electronic
pubmed:day
28
pubmed:volume
107
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
16852-7
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia.
pubmed:affiliation
Division of Hematology-Oncology, Department of Pediatrics, Children's Center for Cancer and Blood Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA 90027-0367, USA. fmuckun@chla.usc.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't