My research program focuses on the pathogenesis of lymphoid malignancy and entails two major arms. First, we have explored the role of NOTCH1 and other oncogenes/tumor suppressors in the genesis and propagation of T-cell acute lymphoblastic leukemia (T-ALL) including studies on downstream target genes/pathways and identifying mechanisms operative in leukemia stem cells. We have addressed these questions in cells from different developmental stages and tissue contexts on the hypothesis that preset epigenetic programs may restrict the oncogenic trajectories available to the cells as they undergo the initial stages of transformation and clonal establishment. Many of our findings have direct clinical relevance in that they serve as basis for the development of rational therapies that target disease-specific phenotypes.
As a second and more recent focus, my lab has explored the use of state-of-the-art mass cytometry (CyTOF) to obtain highly resolved phenotypic maps of heterogeneous cell populations in present in patient lymphoma biopsy samples including both malignant and reactive immune cell compartments. We have used this methodology to characterize intratumoral heterogeneity/subclonal diversity among malignant cell populations and stereotyped or patient-specific immune responses. This work is also of direct clinical relevance in providing detailed phenotypic characterizations that are required in order to define biomarkers for lymphoma classification and prognosis, and monitoring of patient-specific responses to therapy.
Currently Established Methodologies and Approaches
- Synthetic human models of leukemia/lymphoma
- Conventional mouse models of leukemia/lymphoma
- Patient-derived xenograft (PDX) models of leukemia
- Access to clinically annotated primary human lymphoma specimens
- Lentiviral gene transduction, CRISPR/Cas9 gene editing
- RNA-seq, ChIP-seq, single cell RNA-seq, whole exome seq
- High parameter flow cytometry (BD FACSymphony), mass cytometry (CyTOF)
Access to primary human lymphoma specimens
Dr. Weng is the Director of the BCCA Clinical Flow Cytometry Lab and co-manages the Lymphoma Tumor Repository with Drs. Christian Steidl and David Scott. The clinical flow lab accessions nearly 4,000 specimens each year for assessment of lymphoproliferative disease (LPD) including representative portions of ~1,000 excisional lymph node (LN) biopsies. Among these, approximately 100 per year represent follicular lymphoma (FL) and another 100 per year represent diffuse large B cell lymphoma (DLBCL). Single cell suspensions are generated by manual disaggregation and processed for flow cytometric phenotyping using our routine 13-color clinical assay (BD LSRFortessa platform). After diagnostic testing is completed, there are often several to tens of millions of excess viable cells remaining which are prospectively banked with DMSO cryoprotectant. This has been going on for over 2 decades as part of the well established BCCA Lymphoma Program. There are currently over 1,300 cases each of FL and DLBCL in the tumor bank, as well as abundant reactive (normal) lymph nodes to serve as a source of normal control material.