Gene Discovery and the Role of Kinases in Human Bone Marrow Failure and Leukemia
Cytokines play important roles in the regulation of normal hematopoiesis and a balance between the actions of hematopoietic growth factors and myelosuppressive factors is required for optimal production of different hematopoietic cell lineages. We study the role of signaling cascades in the regulation of hematopoiesis and have shown that the p38 MAPK signaling pathway is the dominant cytokine regulated inhibitory pathway in human hematopoiesis. Studies are underway to determine the upstream regulators and downstream effectors of this pathway.
The myelodysplastic syndromes (MDS) are collections of heterogeneous hematological diseases characterized by refractory cytopenias due to ineffective hematopoiesis. These preleukemic disorders are common causes of anemia in the elderly and are rapidly increasing in incidence. Development of effective treatments has been impeded by limited insight into any unifying pathogenic pathways. We have shown that the p38 MAP kinase is constitutively activated in MDS bone marrows. Such activation is uniformly observed in varied morphologic subtypes of low risk MDS and correlates strongly with enhanced apoptosis observed in MDS hematopoietic progenitors. Most importantly, pharmacological inhibition of p38a by a novel small molecule inhibitors can stimulate hematopoiesis in this disease. In addition to studying the mechanism of this important effect by a variety of approaches, we are also studying various other novel small molecule inhibitors in MDS. We are also exploring the role of TGF beta signaling in MDS and the potential of TGF receptor inhibition (by inhibitors or various dominant negative mutants) in restoring hematopoiesis in this disease.
Our lab is also using a combination of high throughput genomic approaches to determine the genes involved in the pathogenesis of human bone marrow disorders. Integrated results of a combination of Gene expression arrays, array based CGH (for detecting deletions and amplifications) and whole genome methylation analysis will be used to determine the relative contribution of genes involved.
Opalinska J, Zhou L, Verma A. A new PML-RARs fusion transcript hints at the important role of PML dysregulation in the pathogenesis of APL. Leuk Lymphoma. 2007 48(3):443-4
Zhou L, Opalinska J, Verma A. p38 MAP kinase regulates stem cell apoptosis in human hematopoietic failure. Cell Cycle. 2007 6(5):534-7.
Navas T, Mohindru M, Estes M, Ma JY, Sokol L, Pahanish P, Parmar S, Haghnazari E, Zhou L, Collins RC, Kerr I, Nguyen A, Xu Y, Platanias LC, List AA, Higgins LS, Verma A. Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Blood. 2006 108(13):4170-7.
Verma A and List A. Cytokine Targets in Myelodysplastic syndromes. Current Hematology Reports 2005 4(6):429-35.
Deonarain R, Verma A, Porter AC, Gewert DR, Platanias LC, Fish EN. Critical roles for IFN-beta in lymphoid development, myelopoiesis, and tumor development: links to tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 2003 100(23):13453-8.
Verma A., Mohindru M., Deb D., Sassano A., Kambhampati S., Minucci S., Ravandi F., Kovakanalu D, Platanias L. “Activation of the Rac1 and p38 MAP kinase pathway in response to Arsenic trioxide.” Journal of Biological Chemistry 2002, 277(47):44988-95.
Verma A, Deb DK, Sassano A, Kambhampati S, Wickrema A, Uddin S, Mohindru M, Van Besien K, Platanias LC. Cutting edge: Activation of the p38 mitogen-activated protein kinase signaling pathway mediates cytokine-induced hemopoietic suppression in aplastic anemia. Journal of Immunology 2002, 168 (12):5984-8.
Verma A, Deb D.K., Sassano A., Uddin S., Varga J., Wickrema A., and Platanias LC. “Activation of the p38 mitogen-activated protein kinase mediates suppressive effects of type I interferons and transforming growth factor-beta on normal hematopoiesis.” Journal of Biological Chemistry 2002, 277(10):7726-35.