Haematologica 2003 - Supplements

preventing phosphorylation of p70S6kinase and 4E-BP1 and,
thus, curtailing cap-dependent translation of transcripts required
for cell cycle transit like cyclins and c-myc (fig 1). However,
transcripts can be translated in a cap-independent fashion if they
contain internal ribosome entry sites (IRES'). C-myc transcripts
contain IRES' and our preliminary results indicate that cyclin D1
transcripts do as well. Thus, a possible explanation for the ability
of AKT to regulate MM cell sensitivity to mTOR inhibitors is
that AKT determines the capability of IRES-specific, capindependent
translation. Indeed, our results support this
hypothesis: Translation of cyclin D1 and c-myc is undetected in
"high-AKT" myeloma cells exposed to mTOR inhibitors while it
is unaffected in "low AKT" myeloma cells (Fig 1). These results
provide a rationale for use of mTOR inhibitors in patients with
mutant ras-containing myeloma clones or those whose myeloma
clones are still IL-6-dependent.
Figure 1:
SEQUENCE OF EVENTS FOLLOWING EXPOSURE OF
MYELOMA CELLS TO MTOR INIBITORS SUCH AS
RAPAMYCIN OR CCI-779. THE MECHANISTIC
DIFFERENCES BETWEEN 'HIGH-AKT' AND 'LOW-AKT'
MYELOMA CELLS ARE SHOWN IN BOLD
P5.3
WNT SIGNALING IN MULTIPLE MYELOMA
Ya-Wei Qiang, Yoshimi Endo, Jeffrey S. Rubin and Stuart
Rudikoff
Laboratory of Cellular and Molecular Biology, National Cancer
Institute, NIH, Bethesda, MD 20892
Wnts comprise a family of secreted proteins that interact with
receptors consisting of a Frizzled (Fz) family member alone or
complexed with LDL receptor related proteins (LRP5/6). Wnt
signaling plays a crucial role in both development and
differentiation and activation of a ‘canonical’ Wnt pathway
resulting in -catenin stabilization is associated with several
types of human cancers the most well studied of which are
colorectal tumors, but also include fibromatosis, gastric, and
hepatocellular carcinoma. -catenin involvement in cancer is
commonly associated with mutations in the amino terminal
region that make the molecule resistant to processing and
degradation. Mutations in other proteins in this pathway, most
notably the APC gene in colon cancer, similarly lead to -catenin
accumulation. A role for other Wnt activated (non-canonical)
pathways in disease has yet to be determined. To date, little is
known about potential Wnt signaling in mature lymphocytes or
lymphoid neoplasia. Herein, we have analyzed Wnt signaling in
mature B cells (lymphomas) and plasma cells (multiple
myeloma). Both Fz and LRP5/6 mRNAs were expressed in
myeloma lines, but LRP5/6 were not observed in lymphomas. In
myelomas, a canonical Wnt signaling pathway was activated
following treatment with Wnt-3a as assessed by accumulation of
-catenin and transcriptional activation, but -catenin levels
actually decreased in lymphoma cells. Wnt-3a treatment further
led to striking morphological changes in myeloma cells
accompanied by rearrangement of the actin cytoskeleton.
Morphological changes resulted in cells developing filopodia-like
processes and becoming attached to culture dishes. The
alterations in morphology were associated with a second Wnt
pathway dependent on Rho activation and could be blocked by an
inhibitor of Rho-associated kinase. These results suggest that Wnt
responsiveness is a stage specific phenomenon in B cell neoplasia
and that the morphological changes associated with Wnt
signaling may play a role in the motility and metastatic potential
of myeloma cells.
P5.4
APOPTOTIC AND SURVIVAL SIGNALING:
THERAPEUTIC IMPLICATIONS
Dharminder Chauhan, Ph.D and Kenneth C. Anderson,
M.D
The Jerome Lipper Multiple Myeloma Center, Department of
Medical Oncology, Dana Farber Cancer Institute, Harvard Medical
School, Boston. E-mail: Dharminder_Chauhan@dfci.harvard.edu
Diverse classes of chemotherapeutic agents induce apoptosis in
multiple myeloma (MM) cells. In contrast, various growth
factors and cytokines present within the bone marrow (BM)
microenvironment trigger MM cell growth and block the
apoptotic effects of drugs. For example, studies in MM cells
have shown that BM-growth factors such as, interleukin-6 (IL-6),
insulin growth factor (IGF) or vascular endothelial growth factor
(VEGF) trigger growth and provide protection against
Dexamethasone (Dex)-induced apoptosis in these cells. Novel
agents that directly and simultaneously target the tumor cell and
its BM microenvironment are required to both enhance drug anti-
MM activity and prevent development of drug-resistance.
Delineation of cellular growth and apoptotic signaling pathways
identify molecule(s) that may serve as novel therapeutic targets.
Our studies have shown that IL-6, IGF or VFGF induce
proliferation of MM cells by activating MAP kinase, PKC and/or
PI3K/Akt pathways. Pretreatment of cells with specific
biochemical inhibitors of these pathways blocks MM cell growth.
Various drugs either alone or in combination with biochemical
inhibitors cause synergistic anti-MM effect via downregulation of
growth pathways. Conversely, novel anti-MM agents such as
Proteasome inhibitor (PS-341), 2-methoxyestradiol (2ME2),
Thalidomide and its immunomodulatory derivatives (IMiDs)
trigger apoptotic signaling that disables the protective effects of
the BM microenvironment, as well as overcomes drug-resistance
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