The Sprouty Proteins The sprouty1 gene is expressed in the developing kidney in a pattern overlapping with the WT1 gene. We found that sprouty inhibits the activation of MAP kinase and likely represents a counter-regulatory signaling molecule that limits the effects of signaling through receptor tyrosine kinases. We demonstrated that Sprouty1 and Sprouty2 inhibit RTK signaling at the level of Ras activation. Current studies focus on knockouts of the Spry genes and the effects of these genes on animal development and signal transduction.
The Molecular Basis of Multiple Myeloma Multiple myeloma (MM) one of the commonest hematological malignancies represents the malignant transformation of plasma cells. For many years the pathogenesis of MM was quite obscure, but over the past decade there has been progress based upon the characterization of consistent chromosomal translocations in MM involving the immunoglobulin heavy chain (IgH). These translocations implicate particular genes in the pathogenesis of myeloma. MMSET (MULTIPLE MYELOMA SET DOMAIN) gene was identified at the breakpoint of the t(4;14) translocation, present in 15-20% of multiple myeloma. MMSET has a SET domain previously identified in histone methyl transferases. We demonstrated that the MMSET protein is strikingly overexpressed in myeloma cells harboring the t(4;14) translocation. Our preliminary data indicate that MMSET has proprieties of a transcriptional co-factor, including nuclear localization, the ability to bind to sequence specific transcription factors 1, transcriptional co-factors and histone deacetylases. Furthermore we found that MMSET has histone methyl transferase activity, modifying histone H3 and H4. These data lead to our overarching hypothesis that aberrant overexpression of MMSET leads to deregulated gene expression in B cells, contributing to the pathogenesis of myeloma.
Molecular Basis of Myeloproliferative Disease Hematological malignancies display a spectrum of phenotypes. At one end is acute leukemia, characterized by proliferation of a population of cells blocked in their differentiation. Myelodysplasia is characterized by blocked differentiation and intramedullary cell death, leading to pancytopenia. In contrast, the myeloproliferative disorders (MPD) are characterized by an excess of well-differentiated cells. Chronic myelogenous leukemia, the archetypal MPD, is associated with the constitutively activated BCR-ABL tyrosine kinase that is specifically targeted by Imatimib. There are a spectrum of MPD represented by aberrant accumulation of each of the respective components of terminally differentiated myeloid lineage cells. These include CML, chronic myelomonocytic leukemia (CMML), agnogenic myeloid metaplasia (AMM) polycythemia vera (PV), essential thrombocythemia (ET), hypereosinophilic syndrome (HES), and systemic mast cell disease (SMCD). Polycythemia vera (PV), a MPD characterized by accumulation of erythrocytes is virtually always associated with a consitutive activating mutation of JAK2 tyrosine kinase. Currently we are 1) Comparing the gene expression profiles of CD34+ cells from PV patients with the profile generated by inserting of mutant JAK2 into human CD34+ cells in culture, 2) Searching for areas of chromosomal changes in PV, MM and ET patients using Affymetrix SNP Chips ; these may represent secondary changes in these diseas. 3) Comparing and contrasting gene expression changes mediated by normal erythropoetic/Jak2 signalign with mutant Jak2 dignalin in terms of proliferation and cell survival pathways. 4) Modeling the action of other activating kinase mutations in MPDs.
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