HDAC
PURPOSE To
study the impact of repetitive (three to four courses) versus a single course
of high-dose cytarabine (HDAC) consolidation therapy
on outcome of patients with acute myeloid leukemia (AML) and inv(16)(p13q22)
or t(16;16)(p13;q22). PATIENTS AND METHODS We examined the cumulative incidence
of relapse (CIR), relapse-free survival (RFS), and overall survival (OS) for 48
adults younger than 60 years with inv(16)/t(16;16) who had attained a complete
remission on one of four consecutive clinical trials and were assigned to
receive HDAC consolidation therapy. Twenty-eight patients were assigned to
either three or four courses of HDAC, and 20 patients were assigned to one course
of HDAC followed by alternative intensive consolidation therapy. Results
Pretreatment features were similar for the two groups. The CIR was
significantly decreased in patients assigned to receive three to four cycles of
HDAC compared with patients assigned to one course (P =.03; 5-year CIR, 43% v
70%, respectively). The difference in RFS also approached statistical
significance (P =.06). In a multivariable analysis that adjusted for potential
confounding covariates, only treatment assignment (three to four cycles of
HDAC) predicted for superior RFS (P =.02). The OS of both groups was similar (P
=.93; 5-year OS, 75% for the three to four cycles of HDAC group v 70% for the
one cycle of HDAC group), reflecting a high success rate with stem-cell
transplantation salvage treatment administered among patients in both treatment
groups. CONCLUSION We conclude that, in AML patients with inv(16)/t(16;16),
repetitive HDAC therapy decreases the likelihood of relapse compared with
consolidation regimens including less HDAC.
PMID: 15020610 [PubMed - in process]
In adult mouse skeletal muscle, beta-myosin heavy chain (betaMyHC) gene expression is primarily restricted to slow type I fibers; however, its expression can be induced in fast type II fibers in response to a sustained increase in load-bearing work (mechanical overload [MOV]). Our previous betaMyHC transgenic and protein-DNA interaction studies have identified an A/T-rich element (betaA/T-rich -269/-258) that is required for slow muscle expression and which potentiates MOV responsiveness of a 293-bp betaMyHC promoter (beta293wt). Despite the GATA/MEF2-like homology of this element, we found binding of two unknown proteins that were antigenically distinct from GATA and MEF2 isoforms. By using the betaA/T-rich element as bait in a yeast one-hybrid screen of an MOV-plantaris cDNA library, we identified nominal transcription enhancer factor 1 (NTEF-1) as the specific betaA/T-rich binding factor. Electrophoretic mobility shift assay analysis confirmed that NTEF-1 represents the enriched binding activity obtained only when the betaA/T-rich element is reacted with MOV-plantaris nuclear extract. Moreover, we show that TEF proteins bind MEF2 elements located in the control region of a select set of muscle genes. In transient-coexpression assays using mouse C2C12 myotubes, TEF proteins transcriptionally activated a 293-bp betaMyHC promoter devoid of any muscle CAT (MCAT) sites, as well as a minimal thymidine kinase promoter-luciferase reporter gene driven by three tandem copies of the desmin MEF2 or palindromic Mt elements or four tandem betaA/T-rich elements. These novel findings suggest that in addition to exerting a regulatory effect by binding MCAT elements, TEF proteins likely contribute to regulation of skeletal, cardiac, and smooth muscle gene networks by binding select A/T-rich and MEF2 elements under basal and hypertrophic conditions.