Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells

Du, Yang; Jenkins, Nancy A.; Copeland, Neal G.

doi:10.1182/blood-2005-03-1113

Cited by 180 publications

(147 citation statements)

References 46 publications

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“…Accordingly, there was an association between retroviral transduction rates and leukemogenesis, with only one reported leukemia among 138 recipients in experiment 3, where double gene transfer was evaluated at 4%. To strengthen the argument, in vitro immortalization of primary hematopoietic cells by insertional mutagenesis, and a correlation to the number of integrations, has been rigorously documented [49], and in vitro expansion of tissue stem cells [27] in the absence of retroviral gene transfer was not associated with malignant transformation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbx1lo hematopoietic stem cells

Cellot

Krošl

Chagraoui

et al. 2007

Experimental Hematology

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Factors that trigger and sustain self-renewal divisions in tissue stem cells remain poorly characterized. By modulating the levels of Hoxb4 and its co-factor Pbx1 in primary hematopoietic cells (Hoxb4 hi Pbx1 lo cells), we report an in vitro expansion of mouse hematopoietic stem cells (HSCs) by 10 5 -fold over 2 weeks, with subsequent preservation of HSC properties. Clonal analyses of the hematopoietic system in recipients of expanded HSCs indicate that up to 70% of Hoxb4 hi Pbx1 lo stem cells present at initiation of culture underwent self-renewal in vitro. In this setting, Hoxb4 and its cofactor did not promote an increase in DNA synthesis, or a decrease in doubling time of Sca1 + Lin − cells when compared to controls. Q-PCR analyses further revealed a down regulation of Cdkn1b (p27 Kip1 ) and Mxd1 (Mad1) transcript levels in Hoxb4 hi Pbx1 lo primitive cells, accompanied by a more subtle increase in c-myc and reduction in Ccnd3 (Cyclin D3). We thus put forward this strategy as an efficient in vitro HSC expansion tool, enabling a further step into the avenue of self-renewal molecular effectors.

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Section: Discussionmentioning

confidence: 99%

Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbx1lo hematopoietic stem cells

Cellot

Krošl

Chagraoui

et al. 2007

Experimental Hematology

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“…Third, overexpression of sPRDM16, but not PRDM16, in myeloid L-G3 cells blocks granulocytic differentiation (17). Finally, aberrant expression of sPRDM16, but not PRDM16, by retroviral insertion promotes immortalization of murine bone marrow progenitors (23). However, a direct comparison of the in vivo leukemogenic potential of the 2 PRDM16 isoforms is still missing.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice

Shing¹,

Trubia²,

Marchesi³

et al. 2007

J. Clin. Invest.

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“…Genomic insertion of marker genes in mouse bone marrow stem cells has resulted in the production of immortalized cell lines in vitro 20 and can produce nonmalignant clonal expansion of hematopoietic stem cells in vivo. 21 Deregulation of cell growth can also proceed further following retroviral transduction, leading to transformation and malignancy following the use of retroviral vectors encoding oncogenes or growth factors, [22][23][24] and the location of viral insertion was thought to play a role in the transforming process.…”

Section: Introductionmentioning

confidence: 99%

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

Westwood

Murray²,

Trivett³

et al. 2008

Gene Ther

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There is considerable concern regarding the transforming potential of retroviral vectors currently used for gene therapy, with evidence that retroviral integration can lead to leukemia in recipients of gene-modified stem cells. However, it is not clear whether retroviral-mediated transduction of T cells can lead to malignancy. We transduced mouse T cells with a Moloney murine retroviral gene construct and transferred them into congenic mice, which were preconditioned to enhance the engraftment of transferred T cells. Recipients were then observed long-term for evidence of cancer. Transferred T cells persisted in mice throughout life at levels up to 17% with gene copy numbers up to 5.89 Â 10 5 per million splenocytes. Mice receiving gene-modified T cells developed tumors at a similar rate as control mice that did not receive T cells, and tumors in both groups of mice were of a similar range of histologies. Hematological malignancies comprised approximately 60% of cancers, and the remaining cancers consisted largely of carcinomas. Importantly, the incidence of lymphomas was similar in both groups of mice, and no lymphomas were found to be of donor T-cell origin. This study indicates that the use of retroviral vectors to transduce T cells does not lead to malignant transformation.

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Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells

Cited by 180 publications

References 46 publications

Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbx1lo hematopoietic stem cells

Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbx1lo hematopoietic stem cells

Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

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