Biomedical Engineering Reference
In-Depth Information
MDS (Merchant et al. 2007). It is anticipated that future studies will further
investigate the role of the Hedgehog pathway in the development of leukemia.
Small-molecule inhibitors which target the Hedgehog pathway (e.g., smooth-
ened inhibitors) are in pre-clinical development and may be an effective tool to
reduce the malignant stem cell pool.
4.3 The Notch Pathway in Leukemia
Notch family members act as receptors for a signal transduction pathway
that controls development and tissue homeostasis by regulating cell fate
and differentiation (Artavanis-Tsakonas et al. 1999). Four Notch receptors
(NOTCH1-4) and five ligands are known. The ligands initiate Notch signaling
by proteolytic cleavage of a metalloprotease called g-secretase from the intra-
cellular domain of the Notch receptor. Increased expression of constitutively
activated NOTCH1 in HSC completely inhibits B-cell development. A gain-of-
function mutation is very common in the NOTCH1 receptor in T-ALL. This
increased NOTCH signaling results in increased T-cell differentiation and self-
renewal in hematopoietic progenitors, leading to transformation to T-ALL
(Aster et al. 2008). Notch inhibitors are already in clinical development.
MK-0752, a g-secretase inhibitor, has already entered a Phase 1 clinical trial
in patients with T-ALL and other leukemias and the results of this study are
awaited (DeAngelo et al. 2006).
4.4 NF-kB in Leukemia
NF-kB is a transcription factor with anti-apoptotic activity which has abnor-
mal expression in both myeloid and lymphoid leukemias (Kordes et al. 2000;
Guzman et al. 2001). NF-kB is constitutively activated in LSCs in AML and
recently studies have focussed on attempting to eradicate AML stem cells using
proteasome inhibitors which induce apoptosis in AML stem cells in association
with inhibition of NF-kB and activation of p-53-related genes (Guzman et al.
2002). In addition, the naturally occurring small-molecule inhibitor partheno-
lide also causes apoptosis in LSC in AML and blast crisis CML, again through
inhibition of NF-kB and activation of p-53 and also increased production of
reactive oxygen species (Guzman et al. 2005, 2007b).
4.5 The HOX Gene Family in Leukemia
The homeodomain-containing transcription factors of the HOX family are pre-
ferentially expressed in primitive self-renewing hematopoietic progenitors and
are downregulated after differentiation. HOX genes are important in normal
