BACKGROUND: The aim of this study was to analyze whether in chronic lymphocytic leukemia the cytosolic release of histone H1.2, a new apoptogenic mechanism induced by DNA damage, was associated with the presence of genetic abnormalities and with the response to treatment. DESIGN AND METHODS: Primary tumoral chronic lymphocytic leukemia cells from 25 patients were investigated for histone H1.2 cytosolic release after treatment with genotoxic (fludarabine, mitoxantrone, etoposide, or X-ray radiation) and non-genotoxic (dexamethasone) agents. Cases were analyzed for the presence of poor-risk genetic alterations, particularly deletions at 17p13 and 11q22. Histone H1.2 release was correlated with the presence of genetic abnormalities and with the best clinical response obtained with standard treatments. RESULTS: DNA-damaging agents induced H1.2 release in a p53-dependent manner which was confirmed by the lack of H1.2 release in p53-deleted cases. Non-DNA-damaging agents induced release of H1.2 in both p53-deleted and non-deleted chronic lymphocytic leukemia cases. Moreover, nuclear H1.2 release was observed after genotoxic and non-genotoxic treatment independently of ATM function. From a clinical standpoint, the lack of histone H1.2 release correlated with resistance to genotoxic treatment. CONCLUSIONS: In chronic lymphocytic leukemia cells, histone H1.2 traffic was dependent on the p53-status after genotoxic treatment, but could also be induced after treatments that acted independently of p53. By contrast, histone H1.2 release did not seem to be dependent on ATM function. Nuclear histone H1.2 release appears to be an important element in apoptosis induction in chronic lymphocytic leukemia, particularly in cases with abnormal p53 function resistant to conventional treatment.
BACKGROUND: The aim of this study was to analyze whether in chronic lymphocytic leukemia the cytosolic release of histone H1.2, a new apoptogenic mechanism induced by DNA damage, was associated with the presence of genetic abnormalities and with the response to treatment. DESIGN AND METHODS: Primary tumoral chronic lymphocytic leukemia cells from 25 patients were investigated for histone H1.2 cytosolic release after treatment with genotoxic (fludarabine, mitoxantrone, etoposide, or X-ray radiation) and non-genotoxic (dexamethasone) agents. Cases were analyzed for the presence of poor-risk genetic alterations, particularly deletions at 17p13 and 11q22. Histone H1.2 release was correlated with the presence of genetic abnormalities and with the best clinical response obtained with standard treatments. RESULTS: DNA-damaging agents induced H1.2 release in a p53-dependent manner which was confirmed by the lack of H1.2 release in p53-deleted cases. Non-DNA-damaging agents induced release of H1.2 in both p53-deleted and non-deleted chronic lymphocytic leukemia cases. Moreover, nuclear H1.2 release was observed after genotoxic and non-genotoxic treatment independently of ATM function. From a clinical standpoint, the lack of histone H1.2 release correlated with resistance to genotoxic treatment. CONCLUSIONS: In chronic lymphocytic leukemia cells, histone H1.2 traffic was dependent on the p53-status after genotoxic treatment, but could also be induced after treatments that acted independently of p53. By contrast, histone H1.2 release did not seem to be dependent on ATM function. Nuclear histone H1.2 release appears to be an important element in apoptosis induction in chronic lymphocytic leukemia, particularly in cases with abnormal p53 function resistant to conventional treatment.
Authors: Liwen Wang; Sean W Harshman; Shujun Liu; Chen Ren; Hua Xu; Larry Sallans; Michael Grever; John C Byrd; Guido Marcucci; Michael A Freitas Journal: Proteomics Date: 2010-12 Impact factor: 3.984
Authors: Yicheng Mao; Georgia Triantafillou; Erin Hertlein; William Towns; Matthew Stefanovski; Xiaokui Mo; David Jarjoura; Mitch Phelps; Guido Marcucci; Ly James Lee; David M Goldenberg; Robert J Lee; John C Byrd; Natarajan Muthusamy Journal: Clin Cancer Res Date: 2012-12-03 Impact factor: 12.531
Authors: Jonathan D Gilthorpe; Fazal Oozeer; Julia Nash; Margarita Calvo; David Lh Bennett; Andrew Lumsden; Adrian Pini Journal: F1000Res Date: 2013-07-08
Authors: Sean W Harshman; Michael M Chen; Owen E Branson; Naduparambil K Jacob; Amy J Johnson; John C Byrd; Michael A Freitas Journal: J Proteomics Date: 2013-09-05 Impact factor: 4.044