Dr. Aly Karsan, MD, FRCPC

Affiliations

Professor, Department of Pathology and Laboratory Medicine, University of British Columbia 
Member, Experimental Medicine, University of British Columbia 
Founding Member, Centre for Blood Research, University of British Columbia 
Member, Stem Cell Network

Professional Profile

After receiving his MD from Queen’s University in Kingston, Ontario and a rotating internship at Lion’s Gate Hospital, North Vancouver, BC, Dr. Karsan practiced medicine in rural BC and the Northwest Territories before working as a volunteer with Médecins Sans Frontières. He then completed his residency in Hematological Pathology at the University of British Columbia (UBC) followed by a Research Fellowship at the University of Washington.

Currently, Dr. Karsan is Professor of Pathology and Laboratory Medicine at UBC, and Distinguished Scientist at Canada's Michael Smith Genome Sciences Centre at BC Cancer. Dr. Karsan has been supported by several prestigious awards over the years, including 10 years as a Clinician-Scientist awardee of the Canadian Institutes of Health Research, 10 years as a Scholar of the Michael Smith Foundation of Health Research and currently as the recipient of the John Auston BC Cancer Foundation Clinical Scientist Award.

Dr. Karsan is internationally recognized in the field of blood cancer research. His translational research lab has generated seminal work on the role of noncoding RNAs and innate immune signaling in blood cancers. He currently leads a team of six principal investigators in a Terry Fox Research Institute Program Project in acute leukemia research. He is a member of various international hematology committees including: the International Working Group for Prognosis in Myelodysplastic Syndromes (MDS), the Experimental Hematology Subcommittee of the Society for Hematopathology, and the Laboratory Assays Working Group for the Myeloid Malignancies Precision Medicine Initiative. In 2002, he co-founded the Centre for Blood Research at UBC with nine other principal investigators.

Dr. Karsan is also a recognized leader in delivering clinical genomic assays. He established the first clinically-accredited Next Generation Sequencing lab in Canada, the Centre for Clinical Genomics (CCG), which was among the first few in the world. The CCG delivers cancer genomic testing to the entire population of BC. This pioneering work in using next generation sequencing (NGS) technologies for clinical delivery has led to the development of various novel technologies for clinical genomic testing including a unique genetic barcoding system to track patient samples, development and implementation of clinical reporting software for NGS, development of a transcriptomic (RNA sequencing) test for leukemia and clinical validation of a non-invasive prenatal test (NIPT) by whole genome sequencing in partnership with the Prenatal Screening Program of BC. He has led clinical trials in leukemia and solid tumour genomics and hereditary cancer diagnostics. These innovations led to a reduction of wait times for hereditary cancer testing, reduced per test costs and have increased the breadth of genes being tested. His work has been recognized with the Health Employers Association of BC (HEABC) Gold Apple award for Innovation.

Research Projects

Overview

The major focus of Dr. Karsan’s lab is to understand post-transcriptional mechanisms driving normal and malignant blood development. In particular, the lab is interested in the ontogeny of myeloid cancers, their progression and resistance to therapy. Ongoing projects including how normal blood cells develop in the embryo through a process of endothelial-to-hematopoietic transition, how dysregulation of noncoding RNAs, methylation status and protein modifications initiate preleukemias and acute leukemia and how these changes can impart resistance to therapies and leukemia relapse. Our lab uses various technologies ranging from genomic analyses of patient cells including low input or single cell methylome, transcriptome and chromatin conformation assays to biochemical and in vitro and in vivo assays to dissect these mechanisms. Details of specific current funded projects are outlined below.

Ontogeny of hematopoietic stem cells

Blood stem cells give rise to all the cells in the circulating blood system, as well as new stem cells. Blood cells that reside in the adult bone marrow first develop in the embryo in a region called the aorta-gonad-mesonephros (AGM).  During mid-gestation blood stem cells differentiate from a specialized subset of endothelial cells, called hemogenic endothelium, lining the aorta. These first blood stem cells then colonize the fetal liver and eventually the bone marrow. Our lab is interested in the signals that drive the process of endothelial-to-hematopoietic transition (EHT). We are currnetly focussing on the role of two genes, Meis1 and Sash1, and their action on endothelial cell intrinsic and extrinsic mechanisms of promoting EHT.

Hematopoietic stem cell aging

As an individual gets older, their blood stem cells do not replenish themselves as well and tend to become more of one type of white blood cell while not producing as many immune cells. This combination leads to more inflammation and inflammation-related diseases including blood cancers, and less ability to fight infections. microRNAs are small molecules that regulate the function of genes. We have found that one of these microRNAs, called miR-146a, decreases with age. In this project, we examine how miR-146a affects blood stem cell aging with a focus on the inflammatory molecules that it regulates in both mouse and human models. We will also determine whether we can reverse the poor function of old blood stem cells by replenishing miR-146a or blocking inflammation. We will also be surveying older individuals to analyze the differences in their transcriptomes to catalogue which other microRNAs might regulate the aging process in blood stem cells. Because the blood system produces many inflammation-related cells and molecules, and because blood travels all over the body, it is likely that by reversing the aging of blood stem cells, we might also help to reduce the impact of aging on other systems such as the heart and brain.

Exploiting pathogenic mechanisms in acute leukemia for clinical translation

Acute leukemias remain one of the most devastating and costly cancers with less than one in five adult patients surviving 10 years. There is a critical need for new approaches for investigating mechanisms of disease pathogenesis and new models to help translate basic findings into new and improved treatments. Specifically, those that effectively target leukemic cells while sparing normal blood-forming cells. The long-term goal of this program, comprising 4 projects and multiple principal investigators, is to better understand the difference between normal blood forming cells and leukemic cells. The program aims to identify and exploit vulnerable disease-causing pathways that may be shared across different types of acute leukemias, which can then be translated into useful biomarkers and treatments that are more effective and less toxic. Of particular interest to our lab is the impact of aberrant ubiquitination on protein stability and activity in driving acute myeloid leukemia (AML).

Mechanisms of therapy resistance and relapse of myeloid blood cancers

Myelodysplastic Syndromes (MDS) cover a wide group of blood cancers. In these studies we are examining how cell state of the (pre)leukemic stem cell and differentiation capacity affect responsiveness and resistance to different therapies. One of the most common genetic changes in MDS is the loss of part of chromosome 5. Some patients with this type of MDS are sensitive to a medicine called Lenalidomide, such that they do not require transfusions. Unfortunately, only about 70 per cent of patients respond, and after two years on treatment, about half the responding patients become resistant to the drug. This project is designed to uncover the mechanisms of resistance to Lenalidomide as well as potentially providing strategies to overcome or bypass resistance. Understanding the mechanism of action of Lenalidomide is not only relevant to MDS, but also to multiple myeloma and other blood cancers.

In related studies we are examining how cell state affects responsiveness and resistance of MDS to the hypomethylating agent 5-azacytidine, as well as the molecular determinants of relapse following stem cell transplant for AML.

More information about the Karsan lab is available here.

Publications

Aly Karsan Google Scholar