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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3301-3308
HEMATOPOIESIS
Proliferation of primitive myeloid progenitors can be
reversibly induced by HOXA10
Jon Mar Björnsson,
Elisabet Andersson,
Patrik Lundström,
Nina Larsson,
Xiufeng Xu,
Ewa Repetowska,
R. Keith Humphries, and
Stefan Karlsson
From the Molecular Medicine and Gene Therapy, Institute
of Laboratory Medicine, Lund University Hospital, Lund, Sweden; and
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver,
Canada.
Recent studies show that several Hox transcription factors are
important for regulation of proliferation and differentiation in
hematopoiesis. Among these is H0XA10, which is selectively expressed at
high levels in the most primitive subpopulation of human
CD34+ bone marrow cells. When overexpressed, H0XA10
increases the proliferation of early progenitor cells and can lead to
the development of myeloid leukemia. To study the effects of H0XA10 on
primitive hematopoietic progenitors in more detail, transgenic mice
were generated with regulatable H0XA10 expression. The transgenic mouse
model, referred to as tetO-HOXA10, contains the
H0XA10 gene controlled by a tetracycline-responsive element and a minimal promoter. Thus, the expression of H0XA10 is
inducible and reversible depending on the absence or presence of
tetracycline or its analog, doxycycline. A retroviral vector containing
the tetracycline transactivator gene (tTA) was used to
induce expression of the H0XA10 gene in bone marrow cells
from the transgenic mice. Reverse transcription-polymerase chain
reaction analysis confirmed regulatable H0XA10 expression in several
transgenic lines. H0XA10 induction led to the formation of
hematopoietic colonies containing blastlike cells and megakaryocytes.
Moreover, the induction of H0XA10 resulted in significant proliferative advantage of primitive hematopoietic progenitors (spleen colony-forming units [CFU-S12]), which was reversible on
withdrawal of induction. Activation of H0XA10 expression in
tet0-H0XA10 mice will therefore govern proliferation of
primitive myeloid progenitors in a regulated fashion. This novel animal
model can be used to identify the target genes of HOXA10 and better
clarify the specific role of HOXA10 in normal and malignant hematopoiesis.
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