Dr. Daniel Starczynowski: 2020 CDP Achievement Award Winner

Dr. Starczynowski

2020 LLS-CDP SCHOLAR ACHIEVEMENT AWARD

co-awardee

 

Dr. Daniel Starczynowski leads a laboratory at Cincinnati Children’s Hospital focused on the intersection of inflammation, innate immune signaling, and hematologic malignancies, with an emphasis on myelodysplastic syndromes and acute myeloid leukemia. Dr. Starczynowski is currently the Katherine Stewart Waters Endowed Chair in Hematologic Malignancies, professor in Pediatrics, and co-leader of the Hematologic Malignancies Program at Cincinnati Children’s Hospital.

 

"I am incredibly humbled and honored to have been a recipient of the Scholar Award from the Leukemia and Lymphoma Society (LLS). The support provided by LLS has allowed our lab to pursue provocative and transformative research directions. For many blood cancers, we still lack fundamental knowledge on their cause. Due to this gap in knowledge, these devastating diseases have few, if any, treatment options. My research program has been dedicated to understanding how dysregulation of inflammatory pathways contributes to myeloid blood cancers. As we learn more about these processes, we hope to inform new therapeutic paradigms for patients with blood cancers. The LLS is immensely important for providing critical and urgently needed funding to expand our knowledge of these diseases and advancing new treatments for the patients."

 

Dr. Starczynowski was awarded the CDP Scholar Award in 2015 for his project titled Investigating genetic and molecular determinants of myelodysplastic syndromes:

Myelodysplastic syndromes (MDS) are malignant diseases of the bone marrow as a result of defective blood-forming cells, otherwise known as hematopoietic stem cells (HSC). For many genes implicated in MDS, it is not known how they contribute to HSC defects, abnormal blood production, and AML, and this gap in knowledge impedes development of novel therapeutics. Population-based studies revealed that chronic immune stimulation increases the risk for MDS. The relevance of the immune pathway to MDS is further supported by studies showing that genes of this pathway are abnormally expressed in MDS. One recurring example is TRAF6, which is overexpressed in MDS HSC. Mice were engineered to mimic MDS HSC with elevated levels of TRAF6. From preliminary data, TRAF6 overexpression in mouse HSC recapitulates aspects of human MDS, making it a valuable resource to understand the pathogenesis of MDS. In this proposal, we will investigate a novel mechanism that contributes to HSC dysfunction in MDS conferred by TRAF6-mediated alterations in mRNA splicing. Our proposal is significant because it connects two common genetic alterations in MDS: chronic immune pathway activation and altered mRNA splicing. This molecular connection, not only has implications in MDS, but also in normal HSC function and host defense mechanisms. We anticipate that the proposed research will advance our knowledge about the molecular and cellular basis of MDS, and reveal novel treatment strategies.

During the award period (2015-2020) the Starczynowski lab has focused on three main long-term objectives: (1) To dissect the genetic, molecular, and cellular underpinnings of MDS and AML, with an emphasis on the role of chronic activation of TLR signaling; (2) To evaluate the developmental requirement of TLR signaling components in normal HSC function; and (3) To use the knowledge gained by our basic research to develop novel therapeutic modalities for the treatment of MDS and AML. Some highlights:

  • characterized aberrant activation of the Toll-like receptor pathway via the TRAF6-IRAK complex in MDS hematopoietic stem and progenitor cells (HSPC)
  • chronic TLR-TRAF6 signaling in HSPCs results in their functional decline; however, an inflammatory milieu affords TLR-TRAF6 primed HSPCs a competitive advantage over wild-type HSPCs
  • tonic and/or stochastic NF-kB signaling is required for HSPC homeostasis in the absence of inflammation or infection
  • identified and developed novel, pre-clinical small molecule inhibitors to suppress TLR-TRAF6 signaling in MDS and AML targeting IRAK1 and IRAK4, two kinases within the TLR-TRAF6 complex

All corresponding author publications during the award period:

  • Nature Immunology. 18(2): 236-245.
  • Cell Reports. 22(5): 1250-1262. PMID: 29386112.
  • Nature Cell Biology. 21(5):640-650. PMID: 3101167.
  • Science Translational Medicine. 4;11(508). PMID: 31484791.
  • Cell Reports. 25;30(8):2776-2790.
  • Journal of Clinical Investigation. 130(4): 2017-2023
  • Nature Immunology. PMID: 32313245.