Loops, Lineage, and Leukemia

Orkin, 1996, for review). Candidature is merited either *Section of Gene Function and Regulation by virtue of their binding to cis-acting regulatory ele-† Leukaemia Research Fund Centre ments of lineage-specific genes or through association Institute of Cancer Research with leukemia-associated chromosomal translocations. Chester Beatty Laboratories While factors identified in this way probably only rep-237 Fulham Road resent a subset of potential regulators, knockouts have London SW3 6JB yielded considerable insight into some of the roles they United Kingdom play in blood cell development and, in particular, the developmental level at which their activity first becomes critical. Thus, in many cases there have been gross or The Identity Problem lethal perturbations in the quality or quantity of mature Adopting a lineage from amongst two or more options effector cells of a given lineage. However, measuring is a fundamental developmental decision in multicellular commitment by a cellular readout of this kind may be organisms—which song to sing from a diverse genetic misleading. For example, while the knockout of GATA-1 repertoire. One way or another, an exclusive option has results in a dramatic loss in red cells, closer inspection to be chosen or imposed. This brief review concerns reveals that the block occurs via an arrest, postcommit-itself with recent insights into this problem in the context ment, at the proerythroblast stage (reviewed in Orkin of the hemopoietic system, where a small pool of multi-and Zon, 1997). While the jury may still be out on the potent hemopoietic stem cells maintain the multiple cell commitment roles of a few factors, such as SCL/TAL lineages that constitute blood. and PU-1 for panhemopoiesis and Ikaros for lymphoid While an extra-or intraembryonic origin for blood stem cells is still being debated, it is clear that blood is a in most instances lineage specification appears to be mesodermal derivative and hemopoietic specification is largely intact at the commitment level when the activity subject to the same concentration gradients of signals of individual factors is ablated by gene knockout. To that pattern the mesoderm and give rise to vasculature, some extent, these data on transcription factor knock-muscle, etc. Several candidate extrinsic signals that pat-outs parallel those obtained in knockout studies of tern the blood component of mesoderm have been iden-growth factors and their receptors. For example, knock-tified, as have some key transcription factors on the outs of EPO or its receptor, while seriously affecting " blood " pathway (Orkin …