Blood, 15 August 2001, Vol. 98, No. 4, pp. 895-895
Welcome to the era of interconnecting pathways
Our understanding of hematopoiesis has evolved from the turn of
the last century when early hematopoietic cells were identified by
morphologic examination of marrow cells after special stains. During
the 1960s and 1970s, Till, McCulloch, Metcalf, and Sachs provided us in
vivo and in vitro clonogenic assays to help dissect the hematopoietic
pathways. Identification of growth factors and their receptors using
these assays markedly propelled our knowledge. This was enhanced by a
variety of separation techniques that took advantage of cell surface
antigens expressed on various hematopoietic lineages. Over the last
several years, focus has turned to identifying transcription factors
that could act as the control center to mediate lineage-specific
differentiation; their importance has been confirmed by their forced
over- or underexpression in hematopoietic cells, both in vitro and in
mice. One family of transcription factors is C/EBP, which is composed
of 6 members (C/EBP-
, -
, -
, -
, -
, and -
). C/EBP-
is robustly expressed in early myelopoiesis and is thought to help
mediate nascent myeloid differentiation. C/EBP- is believed to be
especially important in monocyte-macrophage differentiation.
C/EBP- is important during the later stages of myelopoiesis as
suggested by the following: (1) Specific granule deficiency syndrome
can be caused by a mutation of C/EBP-; affected individuals have
incomplete maturation of their granulocytes, are missing key
granulocyte-specific proteins, and get frequent microbial infections.
(2) C/EBP- knockout mice have the same phenotype. (3) Forced
overexpression of C/EBP- can induce granulocytic differentiation in
myeloid leukemia cell lines and cause expression of granulocyte-
specific proteins in NIH3T3 fibroblasts.
Using all of the above-mentioned techniques, Nakajima and Ihle (page
897) now show that a cytokine (G-CSF) can bind to its cellular receptor
and through an undefined secondary signal can induce expression of
C/EBP- to help mediate myeloid differentiation. They also show that
granulocytic differentiation can be induced through more than one
signaling pathway (STAT3) and that high levels of C-MYC can block both
expression of C/EBP- and myeloid differentiation. This block can be
bypassed by forced expression of C/EBP-. Myelopoiesis is a
complicated symphony composed of a myriad of extracellular stimuli,
numerous intersecting secondary signaling pathways activating a group
of transcription factors that orchestrate expression of a variety of
myeloid specific targets. Armed with instruments of the past including
those acquired from the genome project, we are now in the era of
studying interconnecting, melodious cellular pathways.
H. Phillip Koeffler
Cedars-Sinai Medical Center
