Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77–based mechanism

Chen, Jianguang; Fiskus, Warren; Eaton, Kelly; Fernandez, Pravina; Wang, Yongchao; Rao, Rekha; Lee, Pearl; Joshi, Rajeshree; Yang, Yaping; Kolhe, Ravindra; Balusu, Ramesh; Chappa, Prasanthi; Natarajan, Kavita; Jillella, Anand; Atadja, Peter; Bhalla, Kapil N.

doi:10.1182/blood-2008-08-176024

Cited by 48 publications

(44 citation statements)

References 48 publications

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“…1, H and I). This is consistent with a recent finding in cutaneous T cell lymphoma whereby expression levels of Bcl-2 and Bcl-X L are highly correlated with resistance to Nur77-mediated cell death (50). Furthermore, we were unable to detect any physical interaction between Nur77 and Bcl2 or Bcl-X L in WT DO11.10 cell lines or DO11.10 overexpressing Nur77 ( Figure S5 and S6).…”

Section: Discussionsupporting

confidence: 81%

Phosphorylation of Nur77 by the MEK-ERK-RSK Cascade Induces Mitochondrial Translocation and Apoptosis in T Cells

Wang

Rud²,

Olson

et al. 2009

The Journal of Immunology

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Nur77, an orphan nuclear receptor, plays a key role in apoptosis in T cells. In cancer cell lines, Nur77 can induce apoptosis through the intrinsic apoptotic pathway, but the mechanism by which Nur77 kills T cells remains controversial. In this study, we provide biochemical, pharmacological, and genetic evidence demonstrating that Nur77 induces apoptosis through the activation of the intrinsic pathway in T cells. We also show that Nur77 is a physiological substrate of the MEK-ERK-RSK cascade. Specifically, we demonstrate that RSK phosphorylates Nur77 at serine 354 and this modulates Nur77 nuclear export and intracellular translocation during T cell death. Our data reveal that Nur77 phosphorylation and mitochondrial targeting, regulated by RSK, defines a role for the MEK1/2-ERK1/2 cascade in T cell apoptosis.

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Section: Discussionsupporting

confidence: 81%

Phosphorylation of Nur77 by the MEK-ERK-RSK Cascade Induces Mitochondrial Translocation and Apoptosis in T Cells

Wang

Rud²,

Olson

et al. 2009

The Journal of Immunology

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“…As mDpro is unable to induce apoptosis in thymic cells in our experiments, but is able to suppress thymic tumors, it would seem that p53-dependent apoptosis is not required for the suppression of such tumors. However, as there are reports suggesting otherwise, [37][38][39][40] we conclude that apoptosis is not always required for the prevention of thymic tumors. Furthermore, as mice deleted for the gene encoding p21…”

Section: Discussionsupporting

confidence: 52%

p53-mediated apoptosis prevents the accumulation of progenitor B cells and B-cell tumors

et al. 2009

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We propose that the apoptotic function of p53 has an important role in B-cell homeostasis, which is important for the prevention of B-cell lymphomas. We created a mouse model (mDpro) that lacked residues 58-88 of the proline-rich domain of p53. mDpro is defective for apoptosis, but is able to arrest cell-cycle progression in hematopoietic tissues. mDpro develops late-onset B-cell lymphoma, but not the thymic T-cell tumors found in p53-null mice. Interestingly, mDpro lymphomas comprised incorrectly differentiated B cells. B-cell irregularities were also detected in mDpro before tumor onset, in which aged mice showed an increased population of inappropriately differentiated B cells in the bone marrow and spleen. We predict that by keeping B-cell populations in check, p53-dependent apoptosis prevents irregular B cells from eventuating in lymphomas.

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“…Because this combination had not previously been studied, we selected a dose of DZNep that had been determined to be safe in previously reported studies and combined it with a dose of PS that we had previously reported to be safe and biologically effective. 34,40 NOD/SCID mice, human AML HL-60 cell xenograft studies were sanctioned by protocol approved by the Medical College of Georgia Institutional Animal Care and Use Committee.…”

Section: In Vivo Model Of Amlmentioning

confidence: 99%

Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells

Fiskus

Wang

Sreekumar

et al. 2009

Blood

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337

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Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77–based mechanism

Cited by 48 publications

References 48 publications

Phosphorylation of Nur77 by the MEK-ERK-RSK Cascade Induces Mitochondrial Translocation and Apoptosis in T Cells

Phosphorylation of Nur77 by the MEK-ERK-RSK Cascade Induces Mitochondrial Translocation and Apoptosis in T Cells

p53-mediated apoptosis prevents the accumulation of progenitor B cells and B-cell tumors

Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells

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