Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 352-351
Rebuttal to Enver, Heyworth, and Dexter
THIS PREARRANGED controversy has ended up
with three English authors versus one Australian; the odds seem about
right, regardless of whether it is dice, cricket, or hematopoiesis.
The arguments presented by Enver et al are well-reasoned and the
ambivalent conclusion reached is rather similar to my own. There are
two matters warranting additional comment.
First, all of us accept the data from the recloning of multipotential
cells rather uncritically as indicating random commitment. However,
what was actually observed was asymmetry in the manner in which various
committed progeny were generated. With a genuinely random process, the
probability of progenitor cells of a particular type appearing in a
developing blast colony composed of progenitor cells should increase as
progenitor cell numbers increase in the colony. Current data in our
laboratory indicate no correlation between the total number of
progenitor cells in such colonies and the presence or absence of
progenitors committed to a particular lineage. This seems a powerful
argument against random generation.
Second, the question under discussion has a practical aspect
that needs to be kept in mind. The question is not so much the relative
importance of the roles played by extrinsic regulators or internal gene
programming in commitment, but whether administered agents
either
cytokines or modulators of nuclear transcription factorscan
predictably influence the pattern of generation of committed
progenitors. If this is possible, there are future prospects for
intelligent clinical application. If not, we remain with a hematopoietic system in which selectivity of mature cell production is
achievable using cytokines but at the cost of an inefficient perturbation of populations of less mature precursors, which might be
deleterious in certain clinical situations.
Our present uncertainties regarding the questions under discussion
would be reduced by work in two areas: (1) a solid, in principle,
documentation using normal cells that commitment can be inducible by
cytokines and (2) some serious efforts to establish whether selective
activation of key nuclear transcription factors can be achieved
reproducibly in multipotential cells by extrinsic agents, whatever
their nature.
