BCL-2 inhibition in haematological malignancies: Clinical application and complications.

B-cell lymphoma-2 (BCL-2) family proteins are fundamental regulators of the intrinsic apoptotic pathway which modulate cellular fate. In many haematological malignancies, overexpression of anti-apoptotic factors (BCL-2, BCL-XL and MCL-1) circumvent apoptosis. To address this cancer hallmark, a concerted effort has been made to induce apoptosis by inhibiting BCL-2 family proteins. A series of highly selective BCL-2 homology 3 (BH3) domain mimetics are in clinical use and in ongoing clinical trials for acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL), and multiple myeloma (MM). These inhibitors serve as promising candidates, both as single agents or in combination therapy to improve patient outcomes. In other diseases such as follicular lymphoma, efficacy has been notably limited. There are also clinical problems with BCL-2 family inhibition, including drug resistance, disease relapse, tumour lysis syndrome, and clinically relevant cytopenias. Here, we provide a balanced view on both the clinical benefits of BCL-2 inhibition as well as the associated challenges.

Plasma cell-derived mtDAMPs activate the macrophage STING pathway, promoting myeloma progression.

Mitochondrial damage-associated molecular patterns (mtDAMPs) include proteins, lipids, metabolites, and DNA and have various context-specific immunoregulatory functions. Cell-free mitochondrial DNA (mtDNA) is recognized via pattern recognition receptors and is a potent activator of the innate immune system. Cell-free mtDNA is elevated in the circulation of trauma patients and patients with cancer; however, the functional consequences of elevated mtDNA are largely undefined. Multiple myeloma (MM) relies upon cellular interactions within the bone marrow (BM) microenvironment for survival and progression. Here, using in vivo models, we describe the role of MM cell-derived mtDAMPs in the protumoral BM microenvironment and the mechanism and functional consequence of mtDAMPs in myeloma disease progression. Initially, we identified elevated levels of mtDNA in the peripheral blood serum of patients with MM compared with those of healthy controls. Using the MM1S cells engrafted into nonobese diabetic severe combined immunodeficient gamma mice, we established that elevated mtDNA was derived from MM cells. We further show that BM macrophages sense and respond to mtDAMPs through the stimulator of interferon genes (STING) pathway, and inhibition of this pathway reduces MM tumor burden in the KaLwRij-5TGM1 mouse model. Moreover, we found that MM-derived mtDAMPs induced upregulation of chemokine signatures in BM macrophages, and inhibition of this signature resulted in egress of MM cells from the BM. Here, we demonstrate that malignant plasma cells release mtDNA, a form of mtDAMPs, into the myeloma BM microenvironment, which in turn activates macrophages via STING signaling. We establish the functional role of these mtDAMP-activated macrophages in promoting disease progression and retaining MM cells in the protumoral BM microenvironment.