The bone marrow niche landscape: a journey through aging, extrinsic and intrinsic stressors in the haemopoietic milieu

Inflammation and its effects in the bone marrow microenvironment represent a paradigmatic condition in which the hematopoietic niche and the immune systems, thought to properly sustain blood cell production and distinguish between friend and foe, can actively sustain a corrupted neighborhood within a chronic aberrant inflamed state. The bone marrow niche hijacks the physiologic hematopoiesis. The interactions between the hematopoietic stem cells and the niche in the bone marrow are critical determinants of quiescence. We examined several approaches to confront the available evidence; three key points emerged, pointing to the chronic inflammation process, especially the chronic infection and systemic inflammatory states, as leading causes of hematopoietic stem cell depletion. Clonal hematopoiesis, defined as a relative expansion of individual clones, is caused by somatic alterations in essential hematopoietic genes, which increase stem cell fitness. Moreover, terminal differentiation plays a significant role in progenitor loss and inflammatory signaling, promoting clonal selection and clonal hematopoiesis conditions. Specific myeloid malignancies as paradigmatic examples are discussed as a condition associated with inflammation, including the 5q-syndrome, Philadelphia negative myeloproliferative neoplasms, and chronic myeloid leukemia. Aging with increased fitness and hematopoietic stem cell attrition, extrinsic stress, enhanced stressor-specific fitness, and intrinsic defect across the hematopoietic process represent the route for novel insights in defective hematopoiesis. The discussion in this review also points out that the hematopoietic niches' inflammatory stimulation may affect differentiation patterns and the function of downstream cells

Angiogenesis and Antiangiogenesis in Multiple Myeloma

Multiple myeloma progression is characterized by a dense interaction between cancer cells and bone marrow microenvironment. The interactions of myeloma cells with various stromal cells and extracellular matrix components are the main regulator of the biological processes that underlie the progression of the disease and of the classic symptomatology correlated. The bone marrow of myeloma patients has recognized autocrine and paracrine loops that regulate multiple signaling pathways and the malignant phenotype of plasma cells. One of the pivotal biological processes which are responsible for myeloma progression is the formation of new vessels from existing ones, known as angiogenesis. It represents a constant hallmark of disease progression and a characteristic feature of the active phase of the disease. Near angiogenesis, other two ancestral processes were active in the bone marrow: vasculogenesis and vasculogenic mimicry. These processes are mediated by the angiogenic cytokines, interleukins, and inflammatory cytokines directly secreted by plasma cells and stromal cells. Neovascularization is also mediated by direct interaction between plasma cells and the various components of bone marrow microenvironment. The observation of the increased bone marrow angiogenesis in multiple myeloma and its correlation with disease activity and overall survival led to consider angiogenesis as a new target in the treatment of multiple myeloma

Right Heart Changes Impact on Clinical Phenotype of Amyloid Cardiac Involvement: A Single Centre Study

Amyloidosis is due to deposition of an excessive amount of protein in many parenchymal tissues, including myocardium. The onset of cardiac Amyloidosis (CA) is an inauspicious prognostic factor, which can lead to sudden death. We retrospectively analyzed 135 patients with systemic amyloidosis, admitted to our ward between 1981 and 2019. Among them, 54 patients (46.30% F/53.70% M, aged 63.95 ± 12.82) presented CA at baseline. In 53 patients, it was associated with a multiorgan involvement, while in one there was a primary myocardial deposition. As a control group, we enrolled 81 patients (49.30% F/50.70% M, aged 58.33 ± 15.65) who did not meet the criteria for CA. In 44/54 of patients CA was associated with AL, 5/54 with AA and 3/54 of patients with ATTR, and in 1/54 AL was related to hemodialysis and in 1/54 to Gel-Amyloidosis. The most common AL type was IgG (28/44); less frequent forms were either IgA (7/44) or IgD (2/44), while seven patients had a λ free light chain form. The 32 AL with complete Ig were 31 λ-chain and just one k-chain. CA patients presented normal BP (SBP 118.0 ± 8.4 mmHg; DBP 73.8 ± 4.9 mmHg), while those with nCA had an increased proteinuria (p = 0.02). TnI and NT-proBNP were significantly increased compared to nCA (p = 0.031 and p = 0.047, respectively). In CA patients we found an increased LDH compared to nCA (p = 0.0011). CA patients were also found to have an increased interventricular septum thickness compared to nCA (p = 0.002), a decreased Ejection Fraction % (p = 0.0018) and Doppler velocity E/e' ratio (p = 0.0095). Moreover, CA patients had an enhanced right atrium area (p = 0.0179), right ventricle basal diameter (p = 0.0112) and wall thickness (p = 0.0471) compared to nCA, and an increased inferior cava vein diameter (p = 0.0495) as well. TAPSE was the method chosen to evaluate systolic function of the right heart. In CA subjects very poor TAPSE levels were found compared to nCA patients (p = 0.0495). Additionally, we found a significant positive correlation between TAPSE and lymphocyte count (r = 0.47; p = 0.031) as well as Gamma globulins (r = 0.43, p = 0.033), Monoclonal components (r = 0.72; p = 0.047) and IgG values (r = 0.62, p = 0.018). Conversely, a significant negative correlation with LDH (r = -0.57, p = 0.005), IVS (r = -0.51, p = 0.008) and diastolic function evaluated as E/e' (r = -0.60, p = 0.003) were verified. CA patients had very poor survival rates compared to controls (30 vs. 66 months in CA vs. nCA, respectively, p = 0.15). Mean survival of CA individuals was worse also when stratified according to NT-proBNP levels, using 2500 pg/mL as class boundary (174 vs. 5.5 months, for patients with lower vs. higher values than the median, respectively p = 0.013). In much the same way, a decreased right heart systolic function was correlated with a worse prognosis (18.0 months median survival, not reached in subjects with lower values than 18 mm, p = 0.0186). Finally, our data highlight the potential prognostic and predictive value of right heart alterations characterizing amyloidosis, as a novel clinical parameter correlated to increased LDH and immunoglobulins levels. Overall, we confirm the clinical relevance of cardiac involvement suggests that right heart evaluation may be considered as a new marker for clinical risk stratification in patients with amyloidosis

Vγ9Vδ2 T Cells as Strategic Weapons to Improve the Potency of Immune Checkpoint Blockade and Immune Interventions in Human Myeloma

The advent of immune checkpoint (ICP) blockade has introduced an unprecedented paradigm shift in the treatment of cancer. Though very promising, there is still a substantial proportion of patients who do not respond or develop resistance to ICP blockade. In vitro and in vivo models are eagerly needed to identify mechanisms to maximize the immune potency of ICP blockade and overcome primary and acquired resistance to ICP blockade. Vγ9Vδ2 T cells isolated from the bone marrow (BM) from multiple myeloma (MM) are excellent tools to investigate the mechanisms of resistance to PD-1 blockade and to decipher the network of mutual interactions between PD-1 and the immune suppressive tumor microenvironment (TME). Vγ9Vδ2 T cells can easily be interrogated to dissect the progressive immune competence impairment generated in the TME by the long-lasting exposure to myeloma cellss. BM MM Vγ9Vδ2 T cells are PD-1+ and anergic to phosphoantigen (pAg) stimulation; notably, single agent PD-1 blockade is insufficient to fully recover their anti-tumor activity in vitro indicating that additional players are involved in the anergy of Vγ9Vδ2 T cells. In this mini-review we will discuss the value of Vγ9Vδ2 T cells as investigational tools to improve the potency of ICP blockade and immune interventions in MM

MicroRNAs as a Potential New Preventive Approach in the Transition from Asymptomatic to Symptomatic Multiple Myeloma Disease

Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bonemarrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact onMMtumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

The interaction between the bone marrow microenvironment and plasma cells plays an essential role in multiple myeloma progression and drug resistance. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway in vascular endothelial cells activates and promotes angiogenesis. Moreover, VEGF activates and promotes vasculogenesis and vasculogenic mimicry when it interacts with VEGF receptors expressed in precursor cells and inflammatory cells, respectively. In myeloma bone marrow, VEGF and VEGF receptor expression are upregulated and hyperactive in the stromal and tumor cells. It has been demonstrated that several antiangiogenic agents can effectively target VEGF-related pathways in the preclinical phase. However, they are not successful in treating multiple myeloma, probably due to the vicarious action of other cytokines and signaling pathways. Thus, the simultaneous blocking of multiple cytokine pathways, including the VEGF/VEGFR pathway, may represent a valid strategy to treat multiple myeloma. This review aims to summarize recent advances in understanding the role of the VEGF/VEGFR pathway in multiple myeloma, and mainly focuses on the transcription pathway and on strategies that target this pathway

The bone marrow niche landscape: a journey through aging, extrinsic and intrinsic stressors in the haemopoietic milieu

Inflammation and its effects in the bone marrow microenvironment represent a paradigmatic condition in which the hematopoietic niche and the immune systems, thought to properly sustain blood cell production and distinguish between friend and foe, can actively sustain a corrupted neighborhood within a chronic aberrant inflamed state. The bone marrow niche hijacks the physiologic hematopoiesis. The interactions between the hematopoietic stem cells and the niche in the bone marrow are critical determinants of quiescence. We examined several approaches to confront the available evidence; three key points emerged, pointing to the chronic inflammation process, especially the chronic infection and systemic inflammatory states, as leading causes of hematopoietic stem cell depletion. Clonal hematopoiesis, defined as a relative expansion of individual clones, is caused by somatic alterations in essential hematopoietic genes, which increase stem cell fitness. Moreover, terminal differentiation plays a significant role in progenitor loss and inflammatory signaling, promoting clonal selection and clonal hematopoiesis conditions. Specific myeloid malignancies as paradigmatic examples are discussed as a condition associated with inflammation, including the 5q- syndrome, Philadelphia negative myeloproliferative neoplasms, and chronic myeloid leukemia. Aging with increased fitness and hematopoietic stem cell attrition, extrinsic stress, enhanced stressor-specific fitness, and intrinsic defect across the hematopoietic process represent the route for novel insights in defective hematopoiesis. The discussion in this review also points out that the hematopoietic niches’ inflammatory stimulation may affect differentiation patterns and the function of downstream cells

Filgrastim, lenograstim and pegfilgrastim in the mobilization of peripheral blood progenitor cells in patients with lymphoproliferative malignancies

Patients with lymphoproliferative disorders, candidate to autologous stem cell transplantation (ASCT), require mobilization with chemotherapy and granulocyte colony -stimulating factor (G-CSF). This study looked for differences in hematopoietic peripheral stem cells (HPSCs) mobilization in response to the three available G-CSFs, namely lenograstim, filgrastim, and pegfilgrastim. Between 2000 and 2012, 146 patients (66 M and 80 F) who underwent ASCT for multiple myeloma, non-Hodgkin’s lymphoma or Hodgkin’s lymphoma were studied. All patients received induction therapy and then a mobilization regimen with cyclophosphamide plus lenograstim, or filgrastim, or pegfilgrastim. From days 12 to 14, HPSCs were collected by two to three daily leukaphereses. Our results show that high-dose cyclophosphamide plus lenograstim achieved adequate mobilization and the collection target more quickly and with fewer leukaphereses as compared to filgrastim and pegfilgrastim. No differences between the three regimens were observed regarding toxicity and days to WBC and platelet recovery. Thus, lenograstim may represent the ideal G-CSF for PBSC mobilization in patients with lymphoproliferative diseases. Further studies are needed to confirm these results and better understand the biological bases of these differences