Research
Our studies focus on understanding the molecular biology of the progression of acute leukemias with erythroid differentiation and leukemias arising from antecedent myeloproliferative neoplasms. Particularly, we are interested in dissecting the regulation of JAK2/STAT pathway and the implication of STAT-regulated inflammatory pathways in the erythroid leukemogenesis. We also investigate novel combinational approaches targeting cytokine signaling, DNA methyltransferases and other oncogenic pathways in erythroid leukemias. We finally study the activity of targeted therapies such RAS inhibitors in acute leukemias arising from antecedent myeloid neoplasms.
Our work incorporates signal transduction studies, CRISPR-Cas9 gene editing via viral transduction and electroporation, CRISPR-Cas9 screens, single cell transcriptomic analysis, and cell line and patient-derived xenograft models.
Research Focus
The focus of the Karantanos lab is the dissection of the molecular biology of progression of acute leukemias with erythroid differentiation and acute leukemias arising from antecedent myeloproliferative neoplasms. Specifically, we investigate the regulation of JAK2/STAT pathway and the implication of inflammatory signaling in these diseases incorporating single cell analysis, CRISPR-Cas9 screens, signal transduction studies and erythroid leukemia xenograft mouse models. Our ultimate goal is to identify novel targeted therapies that can improve the outcomes of patients with these lethal subtypes of acute myeloid leukemia.
Investigation of STAT-mediated inflammatory signaling in acute erythroid leukemias
Our hypothesis is that JAK2 regulated STAT-mediated inflammatory signaling and particularly interferon-γ pathway promotes genomic instability in erythroid progenitors mediating erythroid leukemogenesis. We are utilizing single cell analysis, signal transduction and CRISPR-Cas9 gene editing in various in vitro and in vivo models to further study our hypothesis.
Discovery of mechanisms mediating resistance to JAK2 inhibition in erythroid leukemias and post-MPN acute leukemias
While erythroid leukemias and leukemias arising from myeloproliferative neoplasms are relatively sensitive to JAK2 inhibition in vitro, JAK2 inhibitors cannot control these diseases in the clinic. We are utilizing CRISPR-Cas9 screens and cell line and patient-derived xenograft mouse models to identify mechanisms of resistance to JAK2 inhibitors in erythroid leukemias and acute leukemias arising from antecedent myeloproliferative neoplasms.
Developing an antibody-drug conjugate to target CCRL2-expressing leukemia cells
We have found that CCRL2, an atypical chemokine receptor is overexpressed in AML arising from antecedent myeloid neoplasms and particularly acute leukemias with erythroid differentiation. We have developed an antibody-drug conjugate targeting CCRL2 in the surface of leukemia cells showing CCRL2-selective toxicity. We are working on assessing the activity of this agent in various in vivo acute leukemia models and in primary samples from patients with acute leukemia.
Investigation of the activity of RAS inhibition in AML arising from antecedent myeloid neoplasms
RAS mutations are associated with poor outcomes and resistance to current therapies in AML, especially in patients with disease arising from antecedent myeloid neoplasms. We are currently investigating the activity of newly developed RAS inhibitors in various in vitro and in vivo models of RAS mutated secondary AML including primary samples and patient-derived xenografts.
