A5087727695- CAR-T cell therapy research
- Multiple Myeloma Research and Treatments
- Immunotherapy and Immune Responses
- Chronic Myeloid Leukemia Treatments
- Cancer-related gene regulation
- Protein Degradation and Inhibitors
- Epigenetics and DNA Methylation
- RNA Interference and Gene Delivery
- Hematopoietic Stem Cell Transplantation
- Acute Myeloid Leukemia Research
- Chemokine receptors and signaling
- T-cell and B-cell Immunology
- PI3K/AKT/mTOR signaling in cancer
- vaccines and immunoinformatics approaches
- Chronic Lymphocytic Leukemia Research
- Melanoma and MAPK Pathways
- Extracellular vesicles in disease
- Virus-based gene therapy research
- Cytokine Signaling Pathways and Interactions
- Cancer, Hypoxia, and Metabolism
- Cancer Immunotherapy and Biomarkers
- Cell Adhesion Molecules Research
- Polyomavirus and related diseases
- Circular RNAs in diseases
- Single-cell and spatial transcriptomics
Beth Israel Deaconess Medical Center
2019-2025
Harvard University
2019-2025
Alfred Health
2023
Monash University
2023
University of Florence
2013-2021
Hadassah Medical Center
2021
Cancer Research Institute
2021
Tumour Institute of Tuscany
2017-2019
University of Massachusetts Chan Medical School
2014-2017
Mario Negri Institute for Pharmacological Research
2014
Tyrosine kinase inhibitors (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) to TKI-induced killing, which also provides the basis for subsequent emergence TKI-resistant mutants. We report that EZH2, catalytic subunit Polycomb Repressive Complex 2 (PRC2), overexpressed in CML LICs and required colony formation survival cell-cycle progression cell lines. A critical role...
Abstract Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), cause rapid progressing disease a subset patients is still unclear. MM’s progression facilitated by complex interactions with surrounding bone marrow (BM) cells, forming microenvironment that supports tumor growth and drug resistance. Understanding immune key to identifying factors promote MM. To accomplish this, we performed multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells...
Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types cancer, suggesting that inhibition these may limit disease progression relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential survival leukemia (LSCs) in a murine model BCR-ABL-induced chronic myeloid (CML). In absence Alox15, BCR-ABL was unable to induce CML mice. Furthermore, Alox15 deletion...
Abstract Purpose: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating multiple myeloma–reactive lymphocytes and consolidation clinical response following autologous hematopoietic transplant (auto-HCT). Patients Methods: In this randomized phase II trial (NCT02728102), we assessed effect DC/MM fusion vaccination, GM-CSF, lenalidomide maintenance as compared control arms GM-CSF or alone on rates induction myeloma–specific...
This Perspective addresses the interactions of cancer stem cells (CSC) with environment which result in modulation CSC metabolism, and thereby phenotype resistance to therapy. We considered first as a model disease chronic myeloid leukemia (CML), is triggered by well-identified oncogenetic protein (BCR/Abl) brilliantly treated tyrosine kinase inhibitors (TKi). However, TKi are extremely effective inducing remission disease, but unable, most cases, prevent relapse. demonstrated that...
As part of the Multiple Myeloma Research Foundation (MMRF) immune atlas pilot project, we compared cells multiple myeloma bone marrow samples from 18 patients assessed by single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), and cellular indexing transcriptomes epitopes (CITE-seq) to understand concordance measurements among techniques. Cell type abundances are relatively consistent across three approaches, while variations observed in T cells, macrophages, monocytes. Concordance...
We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking polyclonal T cell response against shared and neo-antigens. postulated that the (DC)/AML fusion would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes provide critical substrate for mediated activation.
 Using an immunocompetent murine model, we examined immunologic therapeutic efficacy of vaccination in conjunction...
ABSTRACT Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or sensitivity unclear. We established a harmonized consortium generate an Immune Atlas MM aimed at informing etiology, risk stratification, potential therapeutic strategies. generated transcriptome profile 1,149,344 single cells from bone marrow 263 newly...
Abstract Background: BMT CTN 1401 is a phase II trial of 140 multiple myeloma (MM) patients undergoing autologous hematopoietic cell transplant (HCT) followed by lenalidomide maintenance with or without personalized DC/MM vaccine. Vaccination was associated increased MM-reactive T cells and clonotypic expansion activated 1-year post-HCT. Here, we identify private shared antigenic targets in pre-HCT bone marrow (BM) samples, along corresponding patterns. We also further analyzed the...
While Chimeric Antigen Receptor (CAR) T cell therapy may result in durable remissions recurrent large B lymphoma, persistence is limited and the mechanisms underlying long-term response are not fully elucidated. Using longitudinal single-cell immunoprofiling, here we compare immune landscape remission versus early relapse patients following CD19 CAR infusion NCT02348216 (ZUMA-1) trial. Four weeks post-infusion, both cohorts demonstrate low circulating cells. We observe that associated with...
We analyzed the activity of histone deacetylase inhibitor (HDACi) suberoyl-anilide hydroxamic acid (SAHA) on Kasumi-1 acute myeloid leukemia (AML) cells expressing AML1/ETO. also compared effects SAHA to those valproic (VPA), a short-chain fatty HDACi. and VPA induced H3 H4 acetylation, differentiation massive early apoptosis. The latter were not determined by either drug in AML cell lines, such as NB4 or THP-1, was more rapid effective than increasing acetylation total lysates inducing...
Highlights•ERK5 is constitutively active in chronic myeloid leukemia (CML) cells•ERK5 pathway inhibition reduces the growth of CML cells vitro and vivo•ERK5 strikingly progenitor/stem cell maintenance•The combination ERK5i with imatinib expression stem proteinsSummaryTyrosine kinase inhibitors (TKi) are effective against (CML), but their inefficacy on (LSCs) may lead to relapse. To identify new druggable targets alternative BCR/ABL, we investigated role MEK5/ERK5 LSC maintenance low oxygen,...
Previous studies based on low oxygen concentrations in the incubation atmosphere revealed that metabolic factors govern maintenance of normal hematopoietic or leukemic stem cells (HSC and LSC). The physiological concentration tissues ranges between 0.1 5.0%. Stem cell niches (SCN) are placed tissue areas at lower end this range ("hypoxic" SCN), to which metabolically adapted where they selectively hosted. data reported here indicated driver oncogenic proteins several leukemias suppressed...
We previously showed that incubation of chronic myeloid leukemia (CML) cells in very low oxygen selects a cell subset where the oncogenetic BCR/Abl protein is suppressed and which thereby refractory to tyrosine kinase inhibitors used for CML therapy. In this study, salarin C, an anticancer macrolide extracted from Fascaplysinopsis sponge, was tested as its activity on cells, especially after their atmosphere at 0.1% oxygen. Salarin C induced mitotic cycle arrest, apoptosis DNA damage. also...
The development of molecularly tailored therapeutic agents such as the BCR/ABL-active tyrosine kinase inhibitors (TKi) resulted in an excellent treatment option for chronic myeloid leukemia (CML) patients. However, following TKi discontinuation, disease relapses 40–60% patients, occurrence very likely due to persistence leukemic stem cells that are scarcely sensitive TKi. Nevertheless, still only current CML aim this study was compare effects belonging different generations, imatinib and...