Biomedical Engineering Reference
In-Depth Information
hematopoiesis, self-renewal, and leukemogenesis (Pineault et al. 2002). Many
HOX genes have been linked with the development of acute leukemia, and
chromosomal translocations between NUP98 and HOXA9 or HOXD13 are
reported in AML (Borrow et al. 1996; Raza-Egilmez et al. 1998), with over-
expression of HOXA9 carrying a particularly poor prognosis (Golub et al. 1999).
Overexpression of HOX11 has been reported in T-ALL (Hatano et al. 1991).
The Mixed Lineage Leukemia (MLL) gene is an upstream regulator of the
HOX genes and more than 50 MLL gene rearrangements have been described
with different transcription partners (Krivtsov and Armstrong 2007). It is
believed that the resulting fusion proteins initiate leukemic transformation
through the upregulation of HOX genes (e.g., HOXA9 and co-factor
MEIS1). It has been proposed that self-renewal in LSCs may be regulated by
HOX-dependent pathways (Argiropoulos and Humphries 2007).
4.6 The Polycomb Gene BMI-1 in Leukemia
The polycomb RING-finger protein BMI-1 is an epigenetic chromatin modi-
fier involved in gene repression and is essential for regulating the proliferation
of HSCs and LSCs. In a murine model of AML, the LSCs of Bmi-1-deficient
mice did not result in long-term engraftment and proliferation of cells, but
instead, proceeded to terminal differentiation and apoptosis (Lessard and
Sauvageau 2003). These effects were completely reversed with the addition
of Bmi-1. BMI-1 forms a complex which binds to chromatin and its actions are
thought to be mediated via methylation, deacetylation, and ubiquitination of
core histones. Therefore, inhibitors of these epigenetic modifications, e.g., the
DNA methylation inhibitor 5-azacytidine, histone deacetylase (HDAC) inhi-
bitors, or proteasome inhibitors, could be exploited to inhibit BMI-1 in
clinical studies. Proteasome inhibitors, HDAC inhibitors and 5-azacytidine
have already been assessed in pre-clinical and clinical studies in AML and
MDS (Guzman et al. 2002; Bruserud et al. 2007; Kantarjian et al. 2007; Oki
et al. 2007; Plimack et al. 2007; Attar et al. 2008), although there has been little
evidence for clinical efficacy in the early phase trials, except for 5-azacytidine
in MDS (Kantarjian et al. 2007). HDAC inhibitors induce apoptosis in non-
dividing cells and, very recently, Strauss et al. demonstrated that the HDAC
inhibitor LAQ824 induced apoptosis in CML progenitor cells when used in
combination with the tyrosine kinase inhibitor imatinib (IM) and this was
associated with downregulation of MCL-1 (Strauss et al. 2007).
4.7 The Role of PTEN in Leukemia
A recent study has shown that dependence on the tumor suppressor gene PTEN
separates HSCs from LSCs (Yilmaz et al. 2006). In an in vivo mouse model,
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