Faculty
Oncology Division
Alphabetical list (active faculty):   
John S. Welch

John S. Welch, MD, PhD

Associate Professor

Department of Medicine

Oncology Division

Stem Cell Biology

Research Interests

  • Acute myeloid leukemia
  • Myelodysplastic syndrome
  • Genomics

Contact

  • 314-362-2626 (office)
  • 314-362-9333 (fax)
  • Division of Oncology
    Mail Stop 8007-0057-06
    Washington University
    660 South Euclid Avenue
    St. Louis, MO 63110
  • Southwest Tower, Room 621 (office)
  • Southwest Tower, Room 613L (lab)

Research

The broad goal of our lab is to improve patient care through translational and basic science; we apply clinical insight to inform scientific hypotheses, use molecular technologies to illuminate disease pathogenesis, and then seek to integrate this knowledge back into clinical diagnostics and therapeutics.

Currently, we have three approaches. First, we are integrating broad genomic studies into clinical trials in AML and MDS to identify mechanisms of response and resistance to decitabine. We have observed differences in chemosensitivity within subclones and evolution of subclones during relapse. We found unexpected responses in patients with TP53 mutations and are working to determine the transcriptional consequences of decitabine treatment in TP53 mutated vs. wild type patients as well as the genomic changes associated with relapse. We also seek to determine whether reduction in exome quantified tumor burden could be a better clinical trial end-point than morphologic changes in bone marrow aspirates.

Second, we have found that many nuclear receptors are expressed in hematopoietic and leukemic cells. These are ligand-dependent transcription factors and are thus highly druggable targets. However, there are very few clinical applications for drugs that target the orphan nuclear receptors and the natural ligands for most of these receptors are poorly understood. Our goal is to characterize the distribution and regulation of natural orphan nuclear receptor ligands and to leverage this information to determine which disease states might be susceptible to intervention with an agonist vs. an antagonist. Studies of the retinoid receptors have identified novel ligands and found that the retinoid receptors act as tumor suppressors in myeloid leukemias, and thus might be susceptible to combination retinoid strategies.

Third, we identified cohesins as a novel pathway mutated in AML. We have brought this observation back to the lab and have developed cell and mouse models of cohesin mutations. We are using these to understand the role of this pathway during normal myeloid maturation, how these mutations might contribute to leukemogenesis, and whether we can use this information to identify better treatment options for patients.

Figure A

A. Rapid clearance of the TP53 mutation was noted from the peripheral blood and bone marrow during treatment with decitabine. Quantified mutation clearance from the peripheral blood may provide a more quantitative and reproducible measure of responses compared with morphologic changes in the marrow.

Figure B

B. In silico models of C24:5 docked in RXRA in an active configuration (PDB 1DKF). C24:5 was found to be dynamically regulated in the plasma of mice exposed to myeloid stressors, suggesting leukocyte feedback pathways involving natural RXR ligands that could be therapeutically exploited.