NAD+ METABOLISM RESTRICTION BOOSTS HIGH-DOSE MELPHALAN EFFICACY IN PATIENTS WITH MULTIPLE MYELOMA.

Elevated levels of the nicotinamide adenine dinucleotide (NAD+)-generating enzyme nicotinamide phosphoribosyltransferase (NAMPT) are a common feature across numerous cancer types. Accordingly, we previously reported pervasive NAD+ dysregulation in Multiple Myeloma (MM) cells in association with upregulated NAMPT expression. Unfortunately, albeit being effective in preclinical models of cancer, NAMPT inhibition has proven ineffective in clinical trials due to the existence of alternative NAD+ production routes utilizing NAD+ precursors other than nicotinamide.

Clonal hematopoiesis impacts frailty in newly diagnosed multiple myeloma patients: a retrospective multicenter analysis.

Somatic mutations of hematopoietic cells in the peripheral blood of normal individuals refer to clonal hematopoiesis of indeterminate potential (CHIP), which is associated with a 0.5-1% risk of progression to hematological malignancies and cardiovascular diseases. CHIP has also been reported in Multiple Myeloma (MM) patients, but its biological relevance remains to be elucidated.

Daratumumab in the treatment of C3 glomerulopathy with monoclonal gammopathy: a case report and literature review.

Although rare, C3 glomerulopathy (C3G) is increasingly recognized thanks to the currently available diagnostic skills. C3G is not a single disease but a group of disorders with distinct pathogenesis and progression. Thus, an essential step for its management remains an in-depth characterization of the specific form and the identification of underlying conditions, which may also impact treatment choices as well.

CD38-Induced Metabolic Dysfunction Primes Multiple Myeloma Cells for NAD-Lowering Agents.

Cancer cells fuel growth and energy demands by increasing their NAD biosynthesis dependency, which therefore represents an exploitable vulnerability for anti-cancer strategies. CD38 is a NAD-degrading enzyme that has become crucial for anti-MM therapies since anti-CD38 monoclonal antibodies represent the backbone for treatment of newly diagnosed and relapsed multiple myeloma patients. Nevertheless, further steps are needed to enable a full exploitation of these strategies, including deeper insights of the mechanisms by which CD38 promotes tumorigenesis and its metabolic additions that could be selectively targeted by therapeutic strategies.

Targeting the immune microenvironment in Waldenström macroglobulinemia via halting the CD40/CD40-ligand axis.

Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB-mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype.

Amino acid depletion triggered by ʟ-asparaginase sensitizes MM cells to carfilzomib by inducing mitochondria ROS-mediated cell death.

Metabolic reprogramming is emerging as a cancer vulnerability that could be therapeutically exploitable using different approaches, including amino acid depletion for those tumors that rely on exogenous amino acids for their maintenance. ʟ-Asparaginase (ASNase) has contributed to a significant improvement in acute lymphoblastic leukemia outcomes; however, toxicity and resistance limit its clinical use in other tumors. Here, we report that, in multiple myeloma (MM) cells, the DNA methylation status is significantly associated with reduced expression of ASNase-related gene signatures, thus suggesting ASNase sensitivity for this tumor.

Erythropoietin treatment in chronic phase chronic myeloid leukemia patients treated with frontline imatinib who developed late anemia.

Background: Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined.

Methods: Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated.

Results: Median time from imatinib start to EPO treatment was 42.

The Non-Coding RNA Landscape of Plasma Cell Dyscrasias.

Despite substantial advancements have been done in the understanding of the pathogenesis of plasma cell (PC) disorders, these malignancies remain hard-to-treat. The discovery and subsequent characterization of non-coding transcripts, which include several members with diverse length and mode of action, has unraveled novel mechanisms of gene expression regulation often malfunctioning in cancer. Increasing evidence indicates that such non-coding molecules also feature in the pathobiology of PC dyscrasias, where they are endowed with strong therapeutic and/or prognostic potential.

A simple cytofluorimetric score may optimize testing for biallelic CEBPA mutations in patients with acute myeloid leukemia.

Acute myeloid leukemia with biallelic mutation of CEBPA (CEBPA-dm AML) is a distinct good prognosis entity recognized by WHO 2016 classification. However, testing for CEBPA mutation is challenging, due to the intrinsic characteristics of the mutation itself. Indeed, molecular analysis cannot be performed with NGS technique and requires Sanger sequencing.

Dexamethasone, oxaliplatin and cytarabine (R-DHAOx) as salvage and stem cells mobilizing therapy in relapsed/refractory diffuse large B cell lymphomas.

Cisplatin-containing salvage regimens followed by autologous hematopoietic stem cell (HSC) transplantation are the current standard of care for relapsed or refractory (R/R) lymphomas. We retrospectively analyzed efficacy and stem cell mobilizing activity of oxaliplatin, cytarabine, dexamethasone and rituximab (R-DHAOx) in 53 R/R diffuse large B cell lymphomas (DLBCL) treated in our center (median lines 2, range 2-5; median age 59, range 22-79). Hematological toxicity was manageable and no patients experienced renal impairment.

Depletion of SIRT6 enzymatic activity increases acute myeloid leukemia cells' vulnerability to DNA-damaging agents.

Genomic instability plays a pathological role in various malignancies, including acute myeloid leukemia (AML), and thus represents a potential therapeutic target. Recent studies demonstrate that SIRT6, a NAD-dependent nuclear deacetylase, functions as genome-guardian by preserving DNA integrity in different tumor cells. Here, we demonstrate that also CD34 blasts from AML patients show ongoing DNA damage and SIRT6 overexpression.

Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair.

In the last decade, substantial efforts have been made to identify NAD biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature.

Dual NAMPT and BTK Targeting Leads to Synergistic Killing of Waldenström Macroglobulinemia Cells Regardless of MYD88 and CXCR4 Somatic Mutation Status.

Purpose: Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD pool and is highly expressed in a number of malignancies. FK866, a selective inhibitor of Nampt, depletes intracellular NAD levels, thereby blocking cellular metabolism and triggering sensitization to other drugs and cell death. Here we characterized the antitumor effects of Nampt inhibition in Waldenström macroglobulinemia.

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment.

Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice.

miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth.

Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu.

Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells.

Multiple myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here, we show that the NAD(+)-dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response to genomic stability, and that high SIRT6 levels are associated with adverse prognosis.

Mechanisms and Clinical Applications of Genome Instability in Multiple Myeloma.

Ongoing genomic instability represents a hallmark of multiple myeloma (MM) cells, which manifests largely as whole chromosome- or translocation-based aneuploidy. Importantly, although it supports tumorigenesis, progression and, response to treatment in MM patients, it remains one of the least understood components of malignant transformation in terms of molecular basis. Therefore these aspects make the comprehension of genomic instability a pioneering strategy for novel therapeutic and clinical speculations to use in the management of MM patients.