4.7 Article

CARMA1-and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas

Journal

BLOOD
Volume 127, Issue 14, Pages 1780-1789

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-07-655647

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Funding

  1. Swiss Cancer League
  2. Stiftung zur Krebsbekampfung
  3. Swiss National Science Foundation (SNSF) Sinergia grant [CRSII3_147620]
  4. Deutsche Krebshilfe
  5. Else-Kroner-Fresenius Stiftung
  6. Deutsche Forschungsgemeinschaft (DFG) [EXC 1003]
  7. Swiss National Science Foundation (SNF) [CRSII3_147620] Funding Source: Swiss National Science Foundation (SNF)

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A hallmark of the diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) type, a molecular subtype characterized by adverse outcome, is constitutive activation of the transcription factor nuclear factor-kappa B (NF-kappa B), which controls expression of genes promoting cellular survival and proliferation. Much less, however, is known about the role of the transcription factor activator protein-1 (AP-1) in ABC DLBCL. Here, we show that AP-1, like NF-kB, was controlled by constitutive activation of the B-cell receptor signaling component caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) and/ or the Toll-like receptor signaling component myeloid differentiation primary response gene 88 (MyD88) in ABC DLBCL cell lines. In contrast to germinal center (GC) B-cell (GCB) DLBCL, ABC DLBCL cell lines expressed high levels of the AP-1 family members c-Jun, JunB, and JunD, which formed heterodimeric complexes with the AP-1 family members activating transcription factor (ATF) 2, ATF3, and ATF7. Inhibition of these complexes by a dominant-negative approach led to impaired growth of a majority of ABC DLBCL cell lines. Individual silencing of c-Jun, ATF2, or ATF3 decreased cellular survival and revealed c-Jun/ATF2-dependent control of ATF3 expression. As a consequence, ATF3 expression was much higher in ABC vsGCB DLBCL cell lines. Samples derived from DLBCL patients showed a clear trend toward high and nuclear ATF3 expression in nodal DLBCL of the non-GC or ABC subtype. These findings identify the activation of AP-1 complexes of the Jun/ATF-type as an important element controlling the growth of ABC DLBCL.

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