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Effects of Smoking on Hematopoietic Stem Cell Dysfunction and Hematologic Cancers

Institution: University of California, Irvine
Investigator(s): Gajalakshmi Ramanathan,
Award Cycle: 2019 (Cycle 29) Grant #: T29FT0267 Award: $122,958
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Blood cancers arise from a genetically modified stem cell in the bone marrow. These mutant blood stem cells possess a selective advantage for survival over the normal stem cells in a hostile environment such as inflammation. This transformed stem cell, known as a clone, will then give rise to several blood cells also carrying the mutation, a process termed as “clonal hematopoiesis.” A prolonged inflammatory environment can drive the process of acquiring a mutant stem cell, thus increasing the risk for blood cancer. The presence of these mutant clones has also been found to increase the risk for heart disease. Smoking continues to cause a significant number of cancer-related deaths and is implicated in the development of myeloproliferative neoplasm. E-cigarette use has exploded in recent years while their long-term health effects are unknown. We hypothesize that the components of combustible cigarette smoke and E-cigarette smoke, induce an inflammatory and oxidative environment in the bone marrow that causes depletion of normal blood stem cells but not mutant stem cells. Myeloproliferative neoplasm is a blood cancer that is characterized by overproduction of red blood cells, white blood cells or platelets. We will make use of this model to study the mechanisms of smoke induced changes in bone marrow stem cells and how a common mutation in myeloproliferative neoplasm can aggravate heart disease in the presence of smoke. We demonstrated that bone marrow cells exposed to cigarette smoke extract show increased oxidative stress and reduced growth capacity when compared to untreated cells. We also have data that smoking history significantly aggravates the symptom burden of myeloproliferative neoplasm patients when compared to never-tobacco user patients. In this context, it is important to improve our understanding on how tobacco and E-cigarette smoke impact the leukemic process. Our ultimate goal is to translate our research findings to invest in efforts that will lead to more aggressive counseling for smoking/tobacco use cessation in myeloproliferative neoplasm patients and their family members. Our findings will identify how tobacco- and E-cigarette smoke induced inflammation can alter the blood stem cells and this will be applicable in terms of preventive measures and therapies to reduce inflammation and thus the pre-disposal to cancer and heart disease.