Abstract:
:To further unravel the molecular pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), we performed high-resolution array comparative genomic hybridization on diagnostic specimens from 47 children with T-ALL and identified monoallelic or biallelic LEF1 microdeletions in 11% (5 of 47) of these primary samples. An additional 7% (3 of 44) of the cases harbored nonsynonymous sequence alterations of LEF1, 2 of which produced premature stop codons. Gene expression microarrays showed increased expression of MYC and MYC targets in cases with LEF1 inactivation, as well as differentiation arrest at an early cortical stage of thymocyte development characterized by expression of CD1B, CD1E, and CD8, with absent CD34 expression. LEF1 inactivation was associated with a younger age at the time of T-ALL diagnosis, as well as activating NOTCH1 mutations, biallelic INK4a/ARF deletions, and PTEN loss-of-function mutations or activating mutations of PI3K or AKT genes. These cases generally lacked overexpression of the TAL1, HOX11, HOX11L2, or the HOXA cluster genes, which have been used to define separate molecular pathways leading to T-ALL. Our findings suggest that LEF1 inactivation is an important step in the molecular pathogenesis of T-ALL in a subset of young children.
journal_name
Bloodjournal_title
Bloodauthors
Gutierrez A,Sanda T,Ma W,Zhang J,Grebliunaite R,Dahlberg S,Neuberg D,Protopopov A,Winter SS,Larson RS,Borowitz MJ,Silverman LB,Chin L,Hunger SP,Jamieson C,Sallan SE,Look ATdoi
10.1182/blood-2009-07-234377subject
Has Abstractpub_date
2010-04-08 00:00:00pages
2845-51issue
14eissn
0006-4971issn
1528-0020pii
blood-2009-07-234377journal_volume
115pub_type
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