Network Analysis of miRNA and Cytokine Landscape in Human Hematopoiesis.

The differentiation/maturation trajectories of different blood cell types stemming from a CD34 common ancestor takes place in different biologically relevant multidimensional spaces. Here, we generated microRNA and cytokine profiles from highly purified populations of hematopoietic progenitors/precursors derived from cord blood hematopoietic stem/progenitor cells. MicroRNA and cytokine landscapes were then analyzed to find their mutual relationships under the hypothesis that the highly variable miRNome corresponds to the 'force field' driving the goal of a stable phenotype (here corresponding to the cytokine abundance pattern) typical of each cell kind.

A nanoencapsulated oral formulation of fenretinide promotes local and metastatic breast cancer dormancy in HER2/neu transgenic mice.

Background: Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts.

Single cell analysis of the localization of the hematopoietic stem cells within the bone marrow architecture identifies niche-specific proliferation dynamics.

Introduction: Hematopoietic stem cells (HSC) reside in the bone marrow (BM) in specialized niches which provide support for their self-replication and differentiation into the blood cells. Recently, numerous studies using sophisticated molecular and microscopic technology have provided snap-shots information on the identity of the BM niches in mice. In adults, HSC are localized around arterioles and sinusoids/venules whereas in juvenile mice they are in close to the osteoblasts.

Inhibition of CXCR1/2 reduces the emperipolesis between neutrophils and megakaryocytes in the Gata1 model of myelofibrosis.

Emperipolesis between neutrophils and megakaryocytes was first identified by transmission electron microscopy. Although rare under steady-state conditions, its frequency greatly increases in myelofibrosis, the most severe of myeloproliferative neoplasms, in which it is believed to contribute to increasing the transforming growth factor (TGF)-β microenvironmental bioavailability responsible for fibrosis. To date, the challenge of performing studies by transmission electron microscopy has hampered the study of factors that drive the pathological emperipolesis observed in myelofibrosis.

CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis.

Proinflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution are yet to be fully elucidated. Previously, we identified a critical role for combined constitutive JAK/STAT and aberrant NF-κB proinflammatory signaling in MF development.

Preclinical studies on the use of a P-selectin-blocking monoclonal antibody to halt progression of myelofibrosis in the Gata1 mouse model.

The bone marrow (BM) and spleen from patients with myelofibrosis (MF), as well as those from the Gata1 mouse model of the disease contain increased number of abnormal megakaryocytes. These cells express high levels of the adhesion receptor P-selectin on their surface, which triggers a pathologic neutrophil emperipolesis, leading to increased bioavailability of transforming growth factor-β (TGF-β) in the microenvironment and disease progression. With age, Gata1 mice develop a phenotype similar to that of patients with MF, which is the most severe of the Philadelphia-negative myeloproliferative neoplasms.

The CXCR1/CXCR2 Inhibitor Reparixin Alters the Development of Myelofibrosis in the Mice.

A major role for human (h)CXCL8 (interleukin-8) in the pathobiology of myelofibrosis (MF) has been suggested by observations indicating that MF megakaryocytes express increased levels of hCXCL8 and that plasma levels of this cytokine in MF patients are predictive of poor patient outcomes. Here, we demonstrate that, in addition to high levels of TGF-β, the megakaryocytes from the bone marrow of the mouse model of myelofibrosis express high levels of murine (m)CXCL1, the murine equivalent of hCXCL8, and its receptors CXCR1 and CXCR2. Treatment with the CXCR1/R2 inhibitor, Reparixin in aged-matched mice demonstrated reductions in bone marrow and splenic fibrosis.

Resident Self-Tissue of Proinflammatory Cytokines Rather Than Their Systemic Levels Correlates with Development of Myelofibrosis in Mice.

Serum levels of inflammatory cytokines are currently investigated as prognosis markers in myelofibrosis, the most severe Philadelphia-negative myeloproliferative neoplasm. We tested this hypothesis in the model of myelofibrosis. mice, and age-matched wild-type littermates, were analyzed before and after disease onset.

Under the Control of a Promoter Rescues the Erythroid but Not the Megakaryocytic Phenotype Induced by the Mutation in Mice.

The phenotype of mice carrying the mutation that decreases expression of in erythroid cells and megakaryocytes, includes anemia, thrombocytopenia, hematopoietic failure in bone marrow and development of extramedullary hematopoiesis in spleen. With age, these mice develop myelofibrosis, a disease sustained by alterations in stem/progenitor cells and megakaryocytes. This study analyzed the capacity of driven by a / promoter to rescue the phenotype induced by the mutation in mice.

Role of β1 integrin in thrombocytopoiesis.

Thrombocytopoiesis is a complex process beginning at the level of hematopoietic stem cells, which ultimately generate megakaryocytes, large marrow cells with a distinctive morphology, and then, through a process of terminal maturation, megakaryocytes shed thousands of platelets into the circulation. This process is controlled by intrinsic and extrinsic factors. Emerging data indicate that an important intrinsic control on the late stages of thrombopoiesis is exerted by integrins, a family of transmembrane receptors composed of one α and one β subunit.

TGF-β1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis.

Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGF-β plays a pivotal role in the pathobiology of MF by promoting BM fibrosis and collagen deposition and by enhancing the dormancy of normal hematopoietic stem cells (HSCs). In this study, we show that MF-MKs elaborated significantly greater levels of TGF-β1 than TGF-β2 and TGF-β3 to a varying degree, and we evaluated the ability of AVID200, a potent TGF-β1/TGF-β3 protein trap, to block the excessive TGF-β signaling.

Novel targets to cure primary myelofibrosis from studies on Gata1 mice.

In 2002, we discovered that mice carrying the hypomorphic Gata1 mutation that reduces expression of the transcription factor GATA1 in megakaryocytes (Gata1 mice) develop myelofibrosis, a phenotype that recapitulates the features of primary myelofibrosis (PMF), the most severe of the Philadelphia-negative myeloproliferative neoplasms (MPNs). At that time, this discovery had a great impact on the field because mutations driving the development of PMF had yet to be discovered. Later studies identified that PMF, as the others MPNs, is associated with mutations activating the thrombopoietin/JAK2 axis raising great hope that JAK inhibitors may be effective to treat the disease.