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Key functional role and lineage-specific expression of selected HOXB genes
in purified hematopoietic progenitor differentiation
A Giampaolo, P Sterpetti, D Bulgarini, P Samoggia, E Pelosi, M Valtieri and C Peschle
Department of Hematology-Oncology, Istituto Superiore di Sanita, Rome,
Italy.
Although it is well established that homeobox (HOX) genes play a key role
in normal human embryogenesis, the expression and function of HOX genes in
normal hematopoiesis is largely unknown. We have investigated by reverse
transcriptase-polymerase chain reaction the mRNA expression of HOXB cluster
genes (3' to 5' position in the cluster: from HOXB2 through B9) in 72% to
88% purified hematopoietic progenitor cells (HPCs) from adult peripheral
blood induced in liquid suspension culture to gradual erythroid or
granulopoietic (largely eosinophilic) differentiation and maturation by
differential growth factor (GF) stimulus (ie, low-dose interleukin-3 [IL-3]
and granulocyte-macrophage colony-stimulating factor [GM-CSF] and high-dose
erythropoietin, or saturating amounts of IL-3/GM-CSF, respectively). Only
B3 is expressed in quiescent HPCs. After GF treatment B3 expression is
enhanced in the initial 24 hours and then through differentiation and
maturation in erythroid and granulopoietic cultures. HOXB4 and B5 are
induced at slightly later times and expressed through maturation in both
lineages, whereas B6 is selectively induced in granulocytic
differentiation. B2 is transiently expressed at low level in the
granulopoietic pathway, whereas it is detected only in advanced stages of
erythropoiesis: B7, B8, and B9 are essentially not detected. Functional
studies were performed with antisense phosphorothioate oligomers to HOX
mRNAs and included control analysis of the targeted mRNA. The results are
strictly coherent with the HOX mRNA expression pattern: (1) anti-B3
oligomer (alpha-B3) treatment of purified HPCs induces a striking blockade
of both erythroid and granulomonocytic colony formation (similarly,
alpha-B3 treatment of K562 cell line causes a significant dose-related
inhibition of cell proliferation); (2) alpha-B6 selectively and markedly
inhibits granulomonocytic colony formation; (3) alpha-B4 and alpha-B5 cause
a significant, less pronounced decrease of both colony types; (4) finally,
alpha-B2 and alpha-B7, -B9 exert little and no effect, respectively. These
studies provide novel evidence on the coordinate expression of selected
HOXB cluster genes in erythropoiesis and granulopoiesis, particularly in
the early stages of differentiation: B3 apparently functions as a master
gene in early hematopoiesis, whereas B6 exerts a key selective function in
the granulopoietic pathway.
Volume 84,
Issue 11,
pp. 3637-3647,
12/01/1994
Copyright © 1994 by The American Society of Hematology
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