CD47, or integrin-associated protein, is a cell surface ligand expressed in low levels by nearly all cells of the body. It plays an integral role in various immune responses as well as autoimmunity, by sending a potent "don't eat me" signal to prevent phagocytosis. A growing body of evidence demonstrates that CD47 is overexpressed in various hematological malignancies and its interaction with SIRPα on the phagocytic cells prevents phagocytosis of cancer cells. Additionally, it is expressed by different cell types in the tumor microenvironment and is required for establishing tumor metastasis. Overexpression of CD47 is thus often associated with poor clinical outcomes. CD47 has emerged as a potential therapeutic target and is being investigated in various preclinical studies as well as clinical trials to prove its safety and efficacy in treating hematological neoplasms. This review focuses on different therapeutic mechanisms to target CD47, either alone or in combination with other cell surface markers, and its pivotal role in impairing tumor growth and metastatic spread of various types of hematological malignancies.

EZH2 is highly expressed in multiple myeloma (MM). However, the molecular mechanisms underlying EZH2 overexpression and its role in drug resistance of MM remain undefined. Here we show that EZH2 is upregulated in drug-resistant MM cells and its aberrant overexpression is associated with poor prognosis of MM patients. Overexpression of EZH2 in parental MM cells renders them resistant to anti-myeloma drugs and suppression of EZH2 displays the opposite effects. Using miRNA target scan algorithms, we identify miR-138 as a regulator of EZH2, which is conversely repressed by EZH2-induced H3K27 trimethylation in MM-resistant cell lines and primary tumor cells. Analysis of ChIP-seq dataset and H3K27me3 ChIP reveals that RBPMS is a direct and functionally relevant target of EZH2. RBPMS silencing confers resistance to MM cells and restoration of RBPMS by miR-138 overexpression re-sensitizes the resistant cells to drug. Importantly, in vivo delivery of miR-138 mimics or pharmacological inhibitor of EZH2 in combination with a proteasome inhibitor, bortezomib, induces significant regression of tumors in xenograft model. This study establishes EZH2/miR-138 axis as a potential therapeutic target for MM.

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.