Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1

J Clin Invest. 2008 Sep;118(9):3132-42. doi: 10.1172/JCI35700.

Abstract

Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents / pharmacology
  • Chromosome Aberrations
  • Chromosomes, Human, X*
  • Cyclin D2
  • Cyclins / genetics
  • DNA-Binding Proteins / genetics
  • Gammaretrovirus / metabolism
  • Genetic Therapy / adverse effects*
  • Genetic Therapy / methods*
  • Humans
  • Infant
  • Janus Kinase 3 / genetics
  • LIM Domain Proteins
  • Leukemia, T-Cell / complications
  • Leukemia, T-Cell / etiology*
  • Leukemia, T-Cell / therapy
  • Metalloproteins / genetics
  • Models, Biological
  • Mutation
  • Proto-Oncogene Proteins
  • Receptors, Interleukin-2 / genetics
  • Severe Combined Immunodeficiency / complications
  • Severe Combined Immunodeficiency / therapy*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • CCND2 protein, human
  • Cyclin D2
  • Cyclins
  • DNA-Binding Proteins
  • LIM Domain Proteins
  • LMO2 protein, human
  • Metalloproteins
  • Proto-Oncogene Proteins
  • Receptors, Interleukin-2
  • JAK3 protein, human
  • Janus Kinase 3