Genomes and Genes
VEGF Function in B-CLL
Principal Investigator: Neil Kay
Abstract: B-CLL represents a very common B cell malignancy without a curative approach. Given the aging of the North American population and the continued absence of a means to eradicate this disease, the management remains very difficult. Thus, novel insights into the biology of B-CLL are essential if we are to make progress. Angiogenesis in B-CLL is increasingly implicated as relevant to the biology of the disease process. For example we have found that the neovascularization found in CLL marrow increases as the disease stage progresses and that a VEGF based autocrine pathway induces increases in CLL B cell leukemic apoptotic resistance. This latter aspect we feel is crucial as the biologic hallmark of CLL B cells are their resistance to cell death or apoptosis. The CLL B cell elaborates VEGF that is able to bind to CLL B cell VEGFR-1 and VEGF-R2 type receptors with subsequent enhancement of the leukemic CLL B cell apoptosis resistance. We have gained some insight into the relevant downstream signaling molecules in particular that STAT3 activation and translocation into the CLL nucleus occurs with exposure of CLL B cells to VEGF. In addition, we have found that agents which interrupt the VEGF autocrine pathway, such as Bevacizumab (Avastin) can result in increased CLL B cell killing. In addition we now know that HIF1a a key transcription factor for VEGF is consistently overexpressed in CLL B cells. We have yet to understand the relative importance of each VEGF receptor in signaling and why other mediator molecules such as HIF1a are elevated in CLL B cells. We propose that with further analysis of the role of the VEGF membrane receptors in signaling of CLL B cells, understanding why HIF1a is elevated in these cells and determining what signaling events are critical to CLL B cell apoptosis resistance that we will have important biologic information that will allow us to exploit these findings for therapeutic purposes. Finally, if the administration of Bevacizumab in a clinical trial setting can result in reduction in leukemic CLL B cell levels of relapsed/refractory B-CLL patients and/or generate clinical responses (see appendix 1 for clinical trial) we will validate that a VEGF based pathway is highly relevant to B-CLL progression. Our specific aims in this proposal are: 1) Evaluate the impact and mechanism by which the angiogenic factor, VEGF when secreted by CLL B cells, alters CLL B cell apoptosis and drug resistance. 2) To determine the mechanism for increased production of VEGF in B-CLL B cells cultured under normoxic and hypoxic conditions. 3) Does the VEGF/VEGF-R pathway(s) found in CLL B cells correlate with either clinical and/or critical biologic parameters in B-CLL?
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT
- Bone biopsy derived marrow stromal elements rescue chronic lymphocytic leukemia B-cells from spontaneous and drug induced cell death and facilitates an "angiogenic switch"Neil E Kay
Mayo Clinic, Stabile 628, 200 First Street SW, Rochester, MN 55905, USA
Leuk Res 31:899-906. 2007..These results indicate the interaction between CLL B-cells and marrow stromal elements regulates angiogenic switching and may be linked to disease progression...
- Angiogenesis revisited in CLLNeil E Kay
Leuk Res 31:1459-60. 2007
- Neuropilin-1 is expressed by chronic lymphocytic leukemia B cellsGrzegorz S Nowakowski
Leuk Res 32:1634-6. 2008
- Phase II trials of single-agent anti-VEGF therapy for patients with chronic lymphocytic leukemiaTait Shanafelt
Department of Medicine, Mayo Clinic, Rochester, MN 55902, USA
Leuk Lymphoma 51:2222-9. 2010..No complete or partial remissions were observed. Individually and collectively, these studies indicate that single-agent anti-VEGF therapy has minimal clinical activity for patients with relapsed/refractory CLL...
- Common occurrence of monoclonal B-cell lymphocytosis among members of high-risk CLL familiesLynn R Goldin
Genetic Epidemiology Branch, National Cancer Institute, Bethesda, MD 20892 7236, USA
Br J Haematol 151:152-8. 2010..Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk...
- Platelet-derived growth factor (PDGF)-PDGF receptor interaction activates bone marrow-derived mesenchymal stromal cells derived from chronic lymphocytic leukemia: implications for an angiogenic switchWei Ding
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
Blood 116:2984-93. 2010..These results show that PDGF-PDGFR signaling influences at least the MSC in the microenvironment of CLL and may play a role in the induction of an angiogenic switch known to be permissive for disease progression...
- Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progressionAsish K Ghosh
Division of Hematology, Mayo Clinic, Rochester, MN, USA
Blood 115:1755-64. 2010..This study demonstrates the existence of separate MV phenotypes during leukemic disease progression and underscores the important role of MVs in activation of the tumor microenvironment...
- Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progressionWei Ding
Division of Hematology Oncology, Mayo Clinic, Rochester, MN 55905, USA
Br J Haematol 147:471-83. 2009..These findings support a bi-directional activation between bone marrow stromal cells and CLL B-cells...
- Pretreatment angiogenic cytokines predict response to chemoimmunotherapy in patients with chronic lymphocytic leukaemiaTait D Shanafelt
Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Br J Haematol 146:660-4. 2009..The pretreatment VEGF:TSP ratio also correlated with overall survival (P = 0.008). A pro-angiogenic profile appears associated with diminished response and inferior survival in CLL patients receiving CIT...
- N9986: a phase II trial of thalidomide in patients with relapsed chronic lymphocytic leukemiaNeil E Kay
Mayo Clinic, Rochester, MN 55905, USA
Leuk Lymphoma 50:588-92. 2009....
- Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cellsAsish K Ghosh
Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Blood 113:5568-74. 2009..This is initial evidence that pVHL, without any genetic alteration, can be regulated by microRNA and explains the aberrant autocrine VEGF secretion in CLL...
- The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapyAsish K Ghosh
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
Blood 117:1928-37. 2011..Therefore, we have identified a novel RTK in CLL B cells which appears to work as a docking site for multiple non-RTKs and drives leukemic cell survival signals. These findings highlight a unique target for CLL treatment...