Leukemias following retroviral transfer of multidrug resistance 1 (MDR1) are driven by combinatorial insertional mutagenesis

Modlich, Ute; Kustikova, Olga; Schmidt, Manfred; Rudolph, Cornelia; Meyer, Johann; Li, Zhixiong; Kamino, Kenji; Neuhoff, Nils von; Schlegelberger, Brigitte; Kuehlcke, Klaus; Bunting, Kevin D.; Schmidt, Sonja; Deichmann, Annette; Kalle, Christof von; Fehse, Boris; Baum, Christopher

doi:10.1182/blood-2004-11-4535

Cited by 177 publications

(157 citation statements)

References 42 publications

(64 reference statements)

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“…The kinetics of myeloproliferation development (within a few weeks after transplantation) also makes insertional mutagenesis with subsequent leukemogenesis an unlikely event, as such events tend to take much longer. 48 High tyrosine kinase, that can no longer be regulated in its activity, is the most likely explanation for the myeloproliferations. Whatever the explanation for myeloproliferations in the SFFV promoter group, we further focussed on mice receiving BTK under the control of CD19 and EFS promoters.…”

Section: Erythro-myeloid Proliferation Without Clonal Integration Sitesmentioning

confidence: 99%

Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK

Baert

Pike-Overzet

et al. 2010

Leukemia

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X-linked agammaglobulinemia (XLA) is the most common primary immunodeficiency (PID) in man and caused by mutations in the Bruton's tyrosine kinase (BTK) gene. XLA is characterized by a B-cell differentiation arrest in bone marrow, absence of mature B cells and immunoglobulins (Igs), and recurrent bacterial infections. We used self-inactivating lentiviral vectors expressing codon-optimized human BTK under the control of three different ubiquitous or B cell-specific promoters. BtkÀ/À mice engrafted with transduced cells showed correction of both precursor B-cell and peripheral B-cell development. Lentiviral vectors containing the wildtype BTK sequence did not correct the phenotype. All treated mice with codon-optimized BTK exhibited the recovery of B1 cells in the peritoneal cavity, and of serum IgM and IgG3 levels. Calcium mobilization responses upon B-cell receptor stimulation as well as in vivo responses to T cell-independent antigens were restored. Viral promoters overexpressing BTK 4100-fold above normal resulted in erythro-myeloid proliferations independent of insertional mutagenesis. However, transplantation into secondary BtkÀ/À recipients using cellular promoters resulted in functional restoration of peripheral B cells and IgM levels, without any adverse effects. In conclusion, transduction of human BTK corrects B-cell development and antigen-specific antibody responses in BtkÀ/À mice, thus indicating the feasibility of lentiviral gene therapy for XLA, provided that BTK expression does not vastly exceed normal levels.

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Section: Erythro-myeloid Proliferation Without Clonal Integration Sitesmentioning

confidence: 99%

Correction of B-cell development in Btk-deficient mice using lentiviral vectors with codon-optimized human BTK

Baert

Pike-Overzet

et al. 2010

Leukemia

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“…Leukemias have also been observed to emerge in mice 4-8 months after undergoing transplantation with bone marrow modified with retroviral vectors carrying a multidrug resistance gene transcription unit (18). Clonal dominance of hematopoietic stem cells observed in retroviral marking experiments in rodents was most likely attributable to cis effects of the retroviral integrants on neighboring survival and self-renewal genes, but the kinetics of emergence of the nonmalignant dominant clones also suggests a multistep process (19).…”

Section: Potential Relevance To Cancer and Leukemiamentioning

confidence: 98%

Normal and pathological functions of mammalian retroelements

Deisseroth¹

2005

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the unexpected occurrence of insertional oncogenesis in human clinical trials for primary immunodeficiencies (Hacein-Bey-Abina et al, 2003;Ott et al, 2006;Howe et al, 2008) and in animal models (Li et al, 2002;Kustikova et al, 2005;Modlich et al, 2005) firmly indicated the need to re-examine and modify gene transfer vectors to avoid this serious adverse consequence of gene therapy using integrating vectors. While HIV vectors integrate within genes, MLV integrates within 5 kb of transcriptional start sites, in particular in actively transcribed genes.…”

Section: Insights Into Genotoxicity From Gene-marking Trialsmentioning

confidence: 99%