The Cellular Amount of the Common γ-Chain Influences Spontaneous or Induced Cell Proliferation

Abstract

Mutations of the IL2RG encoding the common ␥-chain (␥ c ) lead to the X-linked SCID disease. Gene correction through ex vivo retroviral transduction restored the immunological impairment in the most of treated patients, although lymphoproliferative events occurred in five of them. Even though in two cases it was clearly documented an insertional mutagenesis in LMO2, it is conceivable that ␥ c could have a role per se in malignant lymphoproliferation. The ␥ c is a shared cytokine receptor subunit, involved also in growth hormone (GH) receptor signaling. Through short interfering RNA or using X-linked SCID B lymphoblastoid cell lines lacking ␥ c , we demonstrate that self-sufficient growth was strongly dependent on ␥ c expression. Furthermore, a correlation between ␥ c amount and the extent of constitutive activation of JAK3 was found. The reduction of ␥ c protein expression also reduced GH-induced proliferation and STAT5 nuclear translocation in B lymphoblastoid cell lines. Hence, our data demonstrate that ␥ c plays a remarkable role in either spontaneous or GH-induced cell cycle progression depending on the amount of protein expression, suggesting a potential role as enhancing cofactor in lymphoproliferation.

Role of Transgene Regulation in Ex Vivo Lentiviral Correction of Artemis Deficiency

“…26,27 Although insertional oncogene activation was reported in three of the leukemic cases it has also been demonstrated that overexpression of the common c chain induces cellular proliferation and may have contributed to the T lymphocyte clonal outgrowth. [26][27][28] Tighter regulation of the common c chain gene may thus reduce the risk of oncogenesis resulting from aberrant overexpression.…”

Cytotoxicity Associated with Artemis Overexpression After Lentiviral Vector-Mediated Gene Transfer

“…Although insertional activation of the LMO2 oncogene was reported in three of the leukemic cases, overexpression of the common g chain also likely contributed to these adverse events (HaceinBey-Abina et al, 2008;Howe et al, 2008). It has subsequently been demonstrated that overexpression of the common g chain induces cellular proliferation that may have ultimately been responsible for the T lymphocyte clonal outgrowth (Amorosi et al, 2009).…”

Immunodeficiency diagnosis: a Mondrian or Pollock scenario?

“…However, the effects of adiponectin in promoting an MM-permissive microenvironment may be multifactorial and additionally include effects on the recruitment of innate immune cells, such as macrophages. 5 These elegant studies suggest a novel concept that the expression of adipokines such as adiponectin in the tumor microenvironment may regulate the permissive state of the marrow microenvironment to MM growth.…”

“…Gamma chain and T-cell development, the role of several ␥-related cytokines in T-cell differentiation and functions, molecular therapy and immune reconstitution through gene transduction, and the general role of the molecule in cell-cycle progression and tumorigenesis are only a few examples that highlight the importance of studies of primary immunodeficiencies (PIDs) that go far beyond the understanding of the cause of a disease. 4,5 Very often, studies in this field highlight shared aspects, which also help unravel It is not surprising that the greater the number of the distinct immunologic disorders, the greater the diversity of presenting signs. Much time elapsed from the paradigm that a severe PID should have been ruled out if the patient had recovered from an infection by the time expected.…”