Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia cells after genotoxic and non-genotoxic treatment

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Haematologica, Vol 93, Issue 1, 75-82 doi: 10.3324/haematol.11546

Induction of histone H1.2 cytosolic release in chronic lymphocytic leukemia

cells after genotoxic and non-genotoxic treatment

Eva Giné, Marta Crespo, Ana Muntañola, Eva Calpe, Joao Baptista, Neus

Villamor, Emili Montserrat, Francesc Bosch

Department of Hematology, Laboratory of Experimental Hematology, Institut

d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic,

University of Barcelona, Barcelona, Spain

Correspondence: Francesc Bosch, MD, Laboratory of Experimental Hematology,

IDIBAPS, Hospital Clínic. Villarroel nº 170, 08036-Barcelona, Spain. E-mail:

fbosch@...

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.