Characterizing the role of ETV6 in lymphoid development and B-cell acute lymphoblastic leukemia predisposition
Citation
Pak, Jensen Joonho. 2022. Characterizing the role of ETV6 in lymphoid development and B-cell acute lymphoblastic leukemia predisposition. Master's thesis, Harvard Medical School.Abstract
B cell acute lymphoblastic leukemia (ALL) is the most common form of pediatriccancer and one of the leading causes of death in children, characterized by clonal
expansion of malignant lymphoid progenitors. While recent studies have identified
a number of genetic risk factors for the development of ALL, our understanding of
the mechanism of susceptibility to the disease remains incomplete. Sequencing
studies have implicated germline ETV6 mutations to predispose patients to
development of blood cancers and particularly to B-cell ALL. However, the specific
role for ETV6 has not been characterized. Here, I investigated the role of germline
ETV6 mutations in human B cell lymphopoiesis and predisposition to ALL. Human
cord blood-derived and adult peripherally mobilized CD34+ cells were edited using
a CRISPR-Cas9 editing strategy that has been established in our laboratory. I
established an optimized in vitro co-culture system for B cell differentiation from
hematopoietic stem cells. I examined the effects of this knockdown on cellular
differentiation, including flow cytometry for phenotypic analysis of different stages
of B cell lymphopoiesis. Perturbation of ETV6, particularly in the ETS domain, in
CD34+ HSPCs produced an altered lymphoid progenitor pool, notably a reduction
in CD45RA+CD33-- and a subtle increase in CD19+-expressing cells at one week
of differentiation. Understanding the role of germline ETV6 variation offers unique
insight into the molecular etiology of and predisposition to ALL, providing future
opportunities for treatment and potential prevention.
Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37375087
Collections
Contact administrator regarding this item (to report mistakes or request changes)