Review

Cell Death and Differentiation (2006) 13, 748–758. doi:10.1038/sj.cdd.4401874; published online 24 February 2006

Targeting NF-kappaB in hematologic malignancies

Edited by G Melino

T Braun1, G Carvalho1, C Fabre1, J Grosjean1, P Fenaux2 and G Kroemer1

  1. 1Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France
  2. 2Hematology Unit, Hôpital Avicenne, AP-HP, Université Paris 13, F-93000 Bobigny, France

Correspondence: G Kroemer, Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, PR1, 39 rue Camille Desmoulins, F-94805 Villejuif, France. Tel: +33 1 42 11 60 46; Fax: +33 1 42 11 60 47; E-mail: kroemer@igr.fr

Received 25 October 2005; Revised 7 December 2005; Accepted 23 December 2005; Published online 24 February 2006.

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Abstract

The transcription factor nuclear factor kappa B (NF-kappaB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-kappaB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-kappaB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-kappaB-activatory kinase IkappaB kinase, of the proteaseome, or of the DNA binding of NF-kappaB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-kappaB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-kappaB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

Keywords:

lymphoid malignancies, myeloid malignancies, apoptosis, bortezomib, IKK antagonists

Abbreviations:

ALL, acute lymphocyte leukemia; AML, acute myeloid leukemia; ATL, adult T-cell leukemia; Bcl-2, B-cell leukemia/lymphoma 2; BL, Burkitt's lymphoma; BMMNC, bone marrow mononuclear cells; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; DBCLs, diffuse large B-cell lymphomas; DISC, death-inducing signaling complex; EBNA, EBV nuclear antigen; EBV, Epstein–Barr virus; FADD, Fas-associated death domain protein; FISH, fluorescence in situ hybridization; FKBP51, FK506-binding protein 51; FLIP, FLICE inhibitory protein; HL, Hodgkin's lymphoma; HRS, Hodgkin and Reed–Sternberg; hTERT, human telomerase reverse transcriptase; HTLV-1, human T-cell leukemia virus type I; IAP, inhibitor of apoptosis protein; IkappaB, inhibitor of NF-kappaB; IKK, IkappaB kinase; IMF, idiopathic myelofibrosis; JAK, janus kinase; LMP, latent membrane protein; LSC, leukemic stem cells; LT, lymphotoxin; MALT, mucosa-associated lymphoid tissue; MDR, multi-drug resistance; MDS, myelodysplastic syndrome; MM, multiple myeloma; MPD, myeloproliferative disorders; NEMO, NF-kappaB essential modulator; NF-kappaB, nuclear factor kappa B; NIK, NF-kappaB-inducing kinase; PI3K, phosphatidylinositol-3 kinase; RANK, receptor activator of NF-kappaB; STAT, signal transducer and activator of transcription; TGF-beta1, transforming growth factor-beta1; TNF, tumor necrosis factor; TRADD, TNF receptor-associated protein with a death domain; VEGF, vascular endothelial growth factor; XIAP, X-chromosome-linked inhibitor of apoptosis protein

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