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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 894-901
Inactivation of a GFP retrovirus occurs at multiple levels in
long-term repopulating stem cells and their differentiated progeny
Christopher A. Klug,
Samuel Cheshier, and
Irving
L. Weissman
From the Department of Pathology and Developmental Biology, Stanford
University Medical Center, Stanford, CA.
Hematopoietic stem cell gene therapy holds promise for the treatment
of many hematologic disorders. One major variable that has limited the
overall success of gene therapy to date is the lack of sustained gene
expression from viral vectors in transduced stem cell populations. To
understand the basis for reduced gene expression at a single-cell
level, we have used a murine retroviral vector, MFG, that expresses the
green fluorescent protein (GFP) to transduce purified populations of
long-term self-renewing hematopoietic stem cells (LT-HSC) isolated
using the fluorescence-activated cell sorter. Limiting dilution
reconstitution of lethally irradiated recipient mice with 100%
transduced, GFP+ LT-HSC showed that silencing of gene
expression occurred rapidly in most integration events at the LT-HSC
level, irrespective of the initial levels of GFP expression. When
inactivation occurred at the LT-HSC level, there was no GFP expression
in any hematopoietic lineage clonally derived from silenced LT-HSC.
Inactivation downstream of LT-HSC that stably expressed GFP
in long-term reconstituted animals was restricted primarily to lymphoid cells. These observations suggest at least 2 distinct mechanisms of silencing retrovirally expressed genes in hematopoietic cells.
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