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Review
. 2016 Oct 4;7(40):66287-66298.
doi: 10.18632/oncotarget.11507.

The BCR-ABL/NF-κB signal transduction network: a long lasting relationship in Philadelphia positive Leukemias

Giovanna Carrà  1 , Davide Torti  1 , Sabrina Crivellaro  1 , Cristina Panuzzo  1 , Riccardo Taulli  2 , Daniela Cilloni  1 , Angelo Guerrasio  1 , Giuseppe Saglio  1 , Alessandro Morotti  1
Affiliations
Review

The BCR-ABL/NF-κB signal transduction network: a long lasting relationship in Philadelphia positive Leukemias

Giovanna Carrà et al. Oncotarget. .

Abstract

The Nuclear Factor-kappa B (NF-κB) family of transcription factors plays a key role in cancer pathogenesis due to the ability to promote cellular proliferation and survival, to induce resistance to chemotherapy and to mediate invasion and metastasis. NF-κB is recruited through different mechanisms involving either canonical (RelA/p50) or non-canonical pathways (RelB/p50 or RelB/p52), which transduce the signals originated from growth-factors, cytokines, oncogenic stress and DNA damage, bacterial and viral products or other stimuli. The pharmacological inhibition of the NF-κB pathway has clearly been associated with significant clinical activity in different cancers. Almost 20 years ago, NF-κB was described as an essential modulator of BCR-ABL signaling in Chronic Myeloid Leukemia and Philadelphia-positive Acute Lymphoblastic Leukemia. This review summarizes the role of NF-κB in BCR-ABL-mediated leukemogenesis and provides new insights on the long lasting BCR-ABL/NF-κB connection.

Keywords: BCR-ABL; CML; IκB-α; NF-κB; NFKBIA.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no competing financial interests to disclose.

Figures

Figure 1
Figure 1. NF-κB pathway
Canonical and non-canonical NF-κB pathways are represented in the left and in the right of the figure respectively. The activation of canonical pathway is mediated by various ligands such as Tumor Necrosis Factor (TNFα), Interleukin-1 (IL-1), or growth factors. The activation relies on the phosphorylation of IκB-α by the IKK complex and subsequent its degradation by the proteasome. Consequently, the RelA/p50 complex translocates to the nucleus where it activates the transcription of target genes. The non-canonical pathway is based on the activation of IKKα by the NF-κB-inducing kinase (NIK), after stimulation. In turn the complex NIK-IKKα phosphorylates the p100 subunit. As a consequence, p100 is processed in a proteasome dependent manner, generating the subunit p52. This event results in the activation of p52-RelB that induces the transcription of distinct target genes.
Figure 2
Figure 2. BCR-ABL/NF-κB crosstalk
Numerous pathways, including Ras, MEKK1, c-Jun N-terminal kinase (JNK) and protein kinase D2 (PKD2) are activated by the Bcr-Abl and converge on NF-κB activation. NF-κB activation is also under the regulation of osteopontin or CUEDC2, as indicated.
Figure 3
Figure 3. NF-κB is regulated by the environment where Ph+ positive cells reside
Interactions between Ph+ stem/progenitor cells and stromal cells and representation of TGF-β and TNF-α networks. Both TGF-β and TNF-α can be secreted by CML cells as part of a autocrine/paracrine loop able to sustain NF-kB signaling. Moreover, Ph+ CML cells can be regulated by TGF-β and TNF-α produced by stromal cells or inflammatory cells. This mechanism may promote NF-kB signaling in a BCR-ABL-independent manner.
Figure 4
Figure 4. Targeting the NF-κB pathway
This Figure reports those drugs that have been shown to modulate NF-κB in Ph+ leukemias. In particular, NF-κB signaling can be modulated by IKK inhibitors (such as PS1145, BAY11-67082, AS602868), proteasome inhibitors (Bortezomid) or with drugs able to act at the transcriptional level (alantolactone, parthenolide).
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