John Welch, M.D., Ph.D.

Assistant Professor
Internal Medicine
Bone & Marrow Transplant

Cancer Biology Program
Molecular Genetics and Genomics Program
Molecular Cell Biology Program

  • 314-362-2626

  • 362-2664

  • 314-362-9333

  • 613 Southwest Tower

  • jwelch@WUSTL.EDU

  • Leukemic alternations of normal hematopoietic self-renewal and differentiation.

Research Abstract:

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 exome sequencing into clinical trials in AML to determine how mutations arise and how chemotherapy alters the subclonal dynamics of leukemia. We have observed evidence of differences in chemosensitivity within subclones and evolution of subclones during relapse. We are working to identify molecular markers that might predict patient-specific response to specific chemotherapies.

Second, 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.

Third, we have found that many of the nuclear receptors are expressed in hematopoietic cells. These are ligand-dependent transcription factors (think of the estrogen receptor). This makes these transcription factors 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. We are characterizing activation patterns and function in normal and stressed hematopoiesis to identify conditions that might be amenable to receptor activation and other conditions that might be more responsive to receptor inhibition. Our initial work has focused on the retinoid receptors, which play important roles in myeloid maturation and the pathogenesis of acute promyelocytic leukemia. We have found that natural RXR ligands are activated during hematopoietic stress and are determining whether we could leverage that information to find new uses for RXR inhibitors.

Selected Publications:

Niu, H., Chacko, J., Hadwiger, G., Welch, J.S. (2015) Absence of natural intracellular retinoids in mouse bone marrow cells and implications for PML-RARA transformation. Blood Cancer Journal. 5: e284. PMID: 25723855.

Welch, J.S. (2014) Mutation Position within Evolutionary Subclonal Architecture in AML. Seminars in Hematology. 51(4): 273-81. PMID: 25311740.

Welch, J.S., Niu, H., Uy, G.L., Westervelt, P., Abboud, C.N., Vij, R., Stockerl-Golstein, K.E., Jacoby, M., Pusic, I., Schroeder, M.A., Dipersio, J.F., Cashen, A.F. (2014) A phase I dose escalation study of oral bexarotene in combination with intravenous decitabine in patients with AML. American Journal of Hematology. 89(8): e103-8. PMID: 24723466.

Wartman, L.D.,* Welch, J.S.*, Uy, G.L, Klco, J.M., Varghese, N., Nagarajan, R., and Ley, T.J. (2012) Expression and function of PML-RARA in the multipotent hematopoietic progenitor cells of Ctsg-PML-RARA mice. PlosOne 7: e46529. PMID: 3466302

Welch, J.S.,* Ley, T.J.*, Link, D.C.* et al. (54 total authors) (2012) The origin and evolution of mutations in Acute Myeloid Leukemia. Cell. 150: 264-278. PMID: 22817890.

Welch JS, Klco JM, Varghese N, Nagarajan R, Ley TJ. Rara haploinsufficiency modestly influences the phenotype of acute promyelocytic leukemia in mice. Blood 2011 117: 2460-8.

Welch JS, Yuan W, Ley TJ. PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice. Journal of Clinical Investigation 2011 121: 1636-1645.

Wartman LD* and Larson DE.* et al. (Welch JS 9th of 33 authors). Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression. Journal of Clinical Investigation 2011 121: 1445-55.

Welch JS* and Westervelt P* et al (22 total authors. Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. JAMA 2011 305: 1577-1584.

Welch JS, Klco JM, Gao F, Procknow E, Uy GL, Stockerl-Goldstein KE, Abboud CN, Westervelt P, DiPersio JF, Hassan A, Cashen AF and Vij R. (2011) Combination Decitabine, Arsenic trioxide and Ascorbic Acid for the Treatment of Myelodysplastic syndrome and Acute Myeloid Leukemia: a phase I study. American Journal of Hematology 2011 86: 796-800.

Last Updated: 9/1/2015 11:16:34 AM

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