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Cell Survival Deregulation in B-Cell Malignancies: Mechanisms and Clinical Targeting in the Era of New Therapeutic Drugs

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Cancer cells are well known to display abnormalities in the regulation of cell cycle and survival. Although solid and hematological cancer cells share these abnormalities, they differ in their origin. In contrast with the majority of solid cancers, mature B-cell malignancies harbor recurrent chromosomal ...

Cancer cells are well known to display abnormalities in the regulation of cell cycle and survival. Although solid and hematological cancer cells share these abnormalities, they differ in their origin. In contrast with the majority of solid cancers, mature B-cell malignancies harbor recurrent chromosomal translocations (with or without gene fusion) that, in some cases, are used as a means to diagnose a specific malignancy. Directly or indirectly, these translocations lead to the deregulated expression of genes involved in cell survival and/or proliferation. For instance, mantle cell lymphoma (MCL), multiple myeloma (MM), Burkitt’s lymphoma (BL) and follicular lymphoma (FL) cells harbor translocations between chromosomes that encode the IgH locus and different genes such as (i) CCND1 in MCL, (ii) CCND1; MAF or NSD2 in MM, (iii) MYC in BL, and (iv) BCL2 in FL. Other mature B-cell malignancies i.e., diffuse large B-cell lymphoma (DLBCL), hairy cell leukemia (HCL), Waldenström Macroglobulinemia (WM), spleen marginal zone lymphoma (SMZL), mucosa-associated lymphoid tissue lymphoma (MALT), chronic lymphocytic leukemia (CLL), do not carry recurrent translocations involving IgH locus but rather, harbor recurrent mutations in several genes involved in the BCR, MAPK, NOTCH, NFkB and mTOR pathways, which govern survival and proliferation. The translocations and/or mutations in driver genes are the first event in the process of malignant transformation, which subsequently requires secondary events such as RB1 deletion, RAS and TP53 mutation/deletion and/or additional chromosomal loss or gain.

Related (e.g. FL) or not (e.g. MM) to chromosomal translocations or gene mutations, mature B-cell malignancies express high levels of anti-apoptotic proteins such as Bcl-2 or Mcl-1, yet are primed to undergo apoptosis. This is correlated with the abundant expression of the pro-apoptotic Bcl-2 family of proteins which interact with anti-apoptotic counterparts at the mitochondria. This mitochondrial priming, which reflects in part that of normal B-cells that are subject to rapid expansion and collapse following infection, opens up strategies for therapeutic targeting. Indeed, B-cell malignancies are sensitive to BH3 mimetic molecules that target the anti- and pro-apoptotic complexes at the mitochondria. Survival deregulation is also related to aberrations in pathways upstream of mitochondria such as BCR or NFkappaB pathways, and these deregulated pathways can also be therapeutically targeted with specific inhibitors (e.g. BTK, proteasome inhibitors).

In this Research Topic, we aim to provide an updated overview of the knowledge on the (intrinsic or environment-mediated) molecular mechanisms controlling cell survival and proliferation that become deregulated in mature B-cell malignancies and how these mechanisms can be targeted therapeutically in order to treat these diseases. We welcome the submission of Original Research, Review and Mini-Review articles that cover the following topics:

1. Deregulation and targeting of Bcl2 network in mature B cell malignancies.
2. Deregulation and targeting of BCR pathway in mature B cell malignancies.
3. Deregulation and targeting of NFkB pathway in mature B cell malignancies.
4. Deregulation and targeting of p53 pathway in mature B cell malignancies.
5. Deregulation and targeting of the Notch pathway in mature B cell malignancies.

Submitted articles are welcome to cover studies on one or several mature B-cell malignancies.


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