Hdac1 and Hdac2 are essential for physiological maturation of a Cx3cr1 expressing subset of T-lymphocytes

Abstract Objective Histone acetylation is an important mechanism in the regulation of gene expression and plays a crucial role in both cellular development and cellular response to external or internal stimuli. One key aspect of this form of regulation is that acetylation marks can be added and removed from sites of regulation very quickly through the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The activity of both HATs and HDACs has been shown to be important for both physiological hematopoiesis as well as during development of hematological neoplasia, such as lymphomas. In the present study we analyzed the effect of knockout of the two HDACs, Hdac1 and Hdac2 in cells expressing the fractalkine receptor (Cx3cr1) on lymphocyte development. Results We report data showing a maturation defect in mice harboring a Cx3cr1 dependent knockout of Hdac1 and 2. Furthermore, we report that these mice develop a T-cell neoplasia at about 4–5 months of age, suggesting that a Cx3cr1 expressing subpopulation of immature T-cells gives rise to T-cell lymphomas in the combined absence of Hdac1 and Hdac2.

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388 POSTER Expression profile of histone deacetylases and histone H4 acetylation in selected B- and T-cell lymphomas

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(06)70393-7 ◽

2006 ◽

Vol 4 (12) ◽

pp. 119-120

Author(s):

L.M. Ipsen ◽

L.M. Gjerdrum ◽

C.B. Poulsen ◽

P.B. Jensen ◽

M. Sehested ◽

...

Keyword(s):

T Cell ◽

Expression Profile ◽

Histone Deacetylases ◽

Histone H4 ◽

T Cell Lymphomas ◽

Histone H4 Acetylation

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Constitutive Expression of Tert in Thymocytes Leads to Increased Incidence and Dissemination of T-Cell Lymphoma in Lck-Tert Mice

Molecular and Cellular Biology ◽

10.1128/mcb.24.10.4275-4293.2004 ◽

2004 ◽

Vol 24 (10) ◽

pp. 4275-4293 ◽

Cited By ~ 67

Author(s):

Andrés Canela ◽

Juan Martín-Caballero ◽

Juana M. Flores ◽

María A. Blasco

Keyword(s):

T Cell ◽

Telomere Length ◽

Cellular Response ◽

Cell Lymphoma ◽

Constitutive Expression ◽

T Cell Lymphoma ◽

Wild Type ◽

T Cell Lymphomas ◽

Peripheral T Cells ◽

Telomere Capping

ABSTRACT Here we describe a new mouse model with constitutive expression of the catalytic subunit of telomerase (Tert) targeted to thymocytes and peripheral T cells (Lck-Tert mice). Two independent Lck-Tert mouse lines showed higher incidences of spontaneous T-cell lymphoma than the corresponding age-matched wild-type controls, indicating that constitutive expression of Tert promotes lymphoma. Interestingly, T-cell lymphomas in Lck-Tert mice were more disseminated than those in wild-type controls and affected both lymphoid and nonlymphoid tissues, while nonlymphoid tissues were never affected with lymphoma in age-matched wild-type controls. Importantly, these roles of Tert constitutive expression in promoting tumor progression and dissemination were independent of the role of telomerase in telomere length maintenance, since telomere length distributions on a single-cell basis were identical in Lck-Tert and wild-type thymocytes. Finally, Tert constitutive expression did not interfere with telomere capping in Lck-Tert primary thymocytes, although it resulted in greater chromosomal instability upon gamma irradiation in Lck-Tert primary lymphocytes than in controls, suggesting that Tert overexpression may interfere with the cellular response to DNA damage.

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