Biology Reference
In-Depth Information
Viruses have also been shown to hijack miRNAs and their modes of
cellular regulation for their own purposes. For instance, Epstein-Barr virus
utilizes miR-155 to transform B cells (
Linnstaedt
et al
., 2011
). Kaposi's
sarcoma-associated herpesvirus encodes an ortholog of miR-155 with over-
lapping target specificity, and this is thought to be involved in its pathoge-
nicity (
Gottwein
et al
., 2007
). Thus, miR-155's ability to regulate cellular
developmental and activation pathways can also be exploited by a variety of
oncogenic viruses, underscoring the importance of miRNAs in hemato-
poietic disease.
Although some miRNAs play oncogenic roles in the hematopoietic
system, others have emerged as powerful tumor suppressors. Mice deficient
in miR-15a/16-1 develop CLL through a mechanism involving derepres-
sion of the survival factor BCL2 (
Klein
et al
., 2010
). miR-146a
mice
develop a range of malignancies, possibly driven by sustained inflammatory
stress (
Boldin
et al
., 2011
). Of note, expression profiling of many different
human cancers indicates that a majority of miRNAs are expressed at
reduced levels in malignant cells consistent with a more common tumor
suppressor role. Dicer has been shown to function as a haploinsufficient
tumor suppressor, with one copy of Dicer leading to a more aggressive
malignancy than a complete loss of Dicer (
Kumar
et al
., 2009
). Perhaps,
reductions in Dicer protein levels lead to lower expression of tumor
suppressor miRNAs while maintaining some expression of relevant onco-
miRs. This might have a stronger impact on cancer development than
complete loss of most miRNAs.
Beyond cell intrinsic roles for miRNAs in the promotion of hemato-
poietic cancers, the miRNA pathway is also necessary for proper function of
the bone marrow “stroma.” The bone marrow “stroma” is comprised of
fibroblasts, adipocytes, osteoblasts, osteoclasts, and endothelial cells that
support stem cell function and hematopoiesis in general. Conditional dele-
tion of Dicer in osteoprogenitors triggers a myelodysplasia that transitions
into a secondary leukemia (
Raaijmakers
et al
., 2010
). This clearly demon-
strates that miRNAs can also impact hematopoiesis and cancer indirectly by
perturbing supporting tissues and niches.
/
5.3. Other hematopoietic disorders
Blood disorders not involving malignant transformation can also be influ-
enced by miRNAs. As mentioned above, an essential function of the
hematopoietic system is delivery of oxygen to tissues. Reductions in RBC
numbers and/or function causes anemia, and a number of miRNAs have
been shown to trigger anemia in mice. A loss of miR-146a or miR-451, or
overexpression of miR-155, miR-125b, or miR-29a, all lead to reduced
RBC levels (
Boldin
et al
., 2011; Han
et al
., 2010; O'Connell
et al
., 2008,
2010a; Patrick
et al
., 2010; Rasmussen
et al
., 2010
). In most of these cases,
