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Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels., In epithelial cancers, rampant DNA double-strand break (DSB) formation followed by activation of the DNA damage response (DDR) occurs in both premalignant and malignant conditions. However, in precancerous settings, senescence [...]

Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL–microenvironment interactions. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation in primary and secondary lymphoid tissues of CD5+ B cells that have the same B cell receptor (BCR) rearrangement. Genetic alterations and different stimuli originating from the microenvironment cooperate in the selection and expansion of the malignant clone. Molecular and functional analyses suggest that stimulation through the BCR affects the destiny of leukemic cells in terms of life or death. Microenvironmental signals are crucial for this process, inducing proliferation and leading to the survival and accumulation of leukemic cells within lymphoid organs. Nevertheless, a number of major biological issues still remain to be solved, including the relationships between cell proliferation and cell accumulation within lymphoid organs as well as the mechanisms that regulate CLL cell migration and recirculation between peripheral blood and lymphoid tissues. We focused on the role played by the cytoskeleton, given its relevance in controlling cellular shape, mobility, and homing. We hypothesize that hematopoietic cell-specific Lyn substrate 1 (HS1), a putative prognostic marker in CLL that interacts with distinct cytoskeleton adapters in leukemic B-lymphocytes, could regulate the CLL cell cytoskeleton. [ABSTRACT FROM AUTHOR]

Despite the recent advances in the therapeutic management of Chronic Lymphocytic Leukemia (CLL) patients, this common B cell malignancy still remains incurable. This SnapShot provides an overview of CLL biology and therapy, with a focus on genetics and microenvironmental interactions, which contribute to disease progression and therapy resistance. To view this SnapShot, open or download the PDF. [ABSTRACT FROM AUTHOR]

Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance. • B-lymphoid cancer cells can escape to venetoclax by overexpressing MCL-1 • Modulation of AMPK/PKA axis and lymphoid transcription drive venetoclax resistance • Venetoclax resistance involves changes in cellular energy metabolism such as OXPHOS • Metabolic modulators can cooperate with venetoclax to overcome resistance Guièze et al. show that resistance to the BCL-2 inhibitor venetoclax in chronic lymphocytic leukemia is associated with complex clonal shifts and identify, in addition to the known involvement by BCL-2 family members, regulators of lymphoid transcription and cellular energy metabolism as resistance drivers. [ABSTRACT FROM AUTHOR]