Malignant transformation of mature T cells after gammaretrovirus mediated transfer of nucleophosmin-anaplastic lymphoma kinase oncogene.
BACKGROUND
Gene therapy has been in use to cure hereditary and acquired diseases by incorporating the desired gene into the cells with the help of gammaretroviral vectors. Despite the success of this therapy in X-linked severe combined immunodeficiency syndrome, few patients developed leukemia as a major adverse event due to retroviral insertional mutagenesis within stem cells. In experimental animals also, retroviral-mediated gene transfer technique resulted in the development of leukemia. On the other hand, evidence suggests that mature T cells (TC) are relatively resistant to transformation even after retroviral-mediated transfer of potent oncogenes Tcl1, ΔTrkA and LMO2 with no reported side effects yet.


OBJECTIVE
To further address the safety issue for TC use in gene therapy, this study investigated susceptibility of mature polyclonal TC to malignant transformation by the retroviral-mediated transfer of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogene.


METHODS
Wild-type mature TC, isolated from C57BL/6 donor mice (genetic background Ly5.1) were transduced with gamma-retroviral vectors encoding the potent TC oncogene NPM-ALK or the control vector enhanced green fluorescent protein eGFP. The cells were then transplanted into RAG-1 deficient recipient mice (genetic background Ly5.2).


RESULTS
Two out of five mice from NPM-ALK oncogene group developed leukemia/lymphoma after latency periods (153 and 250 days, respectively). None of the mice from the control group developed any malignancy throughout the observational period.


CONCLUSIONS
Mature polyclonal TC are relatively susceptible to malignant transformation after gamma-retroviral mediated transfer of NPM-ALK oncogene; hence safety of TC use in gene therapy should be further investigated to avoid the possible side-effect of development of leukemia/lymphoma.
Pathology Department, College of Medicine, King Faisal University, AL Ahsa, Saudi Arabia.
Ashok
A
Kumar
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D017988:Gammaretrovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D007938:Leukemia / Q000473:pathology; D008223:Lymphoma / Q000473:pathology; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D015513:Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013601:T-Lymphocytes / Q000473:pathology* / Q000821:virology*; D014161:Transduction, Genetic
D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000090243:Nucleophosmin; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases