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Functional identification of secondary mutations inducing autonomous growth in synergy with a truncated interleukin-3 receptor: Implications for multi-step oncogenesis
Elsevier Journal Backfiles on ScienceDirect (DFG Nationallizenzen)
Beschreibungen/Notizen
A truncated common β chain (Δβ
C) of the interleukin-3 (IL-3) receptor complex was previously identified as a key factor in inducing autonomous growth of IL-3–independent mutants. Expression of Δβ
C in IL-3–dependent hematopoietic cells does not result in immediate factor-independent growth, but increases the frequency of obtaining autonomous mutants by three to four orders of magnitude. This study was designed to delineate the mechanisms by which Δβ
C increases the frequency to autonomous growth.
Retroviral vectors were used to express Δβ
C into IL-3–dependent myeloid cells, which were then tested for factor-independent growth. To determine if secondary genetic events were required for conversion to autonomous growth, elements of the Cre-loxP recombinant system were used to excise Δβ
C in factor-independent clones.
Excision of Δβ
C in factor-independent clones revealed two types of phenotypes: reversion to factor-dependent growth (1/8) or continued IL-3–dependent growth (7/8). Analysis of cells that remained factor independent revealed constitutive activation of STAT5, not observed in factor-dependent revertants. Analysis of revertant cells demonstrated the presence of interacting secondary mutations that synergize with Δβ
C-induced proliferation. A cysteine residue within the truncated extracellular domain of Δβ
C was also found to be required for its oncogenic potential, supporting a model of dimerization for receptor activation.
The high incidence of obtaining factor-independent mutants from cells expressing Δ
β
C
results from the selection of mutations that either complement Δ
β
C
expression to promote proliferation or that singly or in synergy with other secondary mutations negate the requirement of Δ
β
C
expression for proliferation.