Premium
Stem Cell Gene Transfer: Insights into Integration and Hematopoiesis from Primate Genetic Marking Studies
Author(s) -
DUNBAR CYNTHIA E.
Publication year - 2005
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1349.023
Subject(s) - biology , haematopoiesis , stem cell , cd34 , genetic enhancement , progenitor cell , viral vector , hematopoietic stem cell , gene , virology , cancer research , genetics , recombinant dna
A bstract : Genetic marking strategies in the nonhuman primate model have elucidated a number of principles with relevance to implementation of clinical stem cell therapies, including the lineage potential, number, and life span of hematopoietic stem and progenitor cells. The recent occurrence of leukemias likely related to insertional activation of a proto‐oncogene in two patients with X‐severe combined immunodeficiency (SCID) syndromes treated with CD34 + cells transduced with retroviral vectors expressing the corrective common γ cytokine receptor gene has refocused attention on the issue of retroviral integration. We have analyzed >1500 independent insertions from rhesus macaques transplanted with CD34 + cells transduced with either MLV or SIV vectors. Of these, 46 rhesus macaques followed long term have not had progression to leukemia, abnormal hematopoiesis, or clonal hematopoiesis. However, the pattern of both MLV and SIV integrants in cells of these animals was found to be highly nonrandom, with a propensity for insertions of both vectors within genes: for MLV particularly near the transcription start site, and for SIV particularly in gene‐dense regions.