Derek Lynn Stirewalt

Appointments and Affiliations

 
 
Fred Hutchinson Cancer Research Center
Clinical Research Division
Associate Member, Appointed: 2010
University of Washington
School of Medicine
Medicine
Oncology
Associate Professor, Appointed: 2010
Professional Headshot of M. Robyn Andersen

Mailing Address

D5-112
1100 Fairview Ave. N.
Seattle, Washington 98109
United States

Contact

Phone: (206) 667-5386
dstirewa@fhcrc.org

Research Interests

The overall goals of the Stirewalt lab are to identify novel biomarkers for hematopoietic disease development and to understand how these biomarkers may function to promote hematopoietic malignancies. Together, this work strives to improve the care of patients at risk and with hematopoietic malignancies. To meet these goals, we have 4 primary research focuses.

1. Development and Refinement of FLT3 Mutations as an AML Prognostic Biomarker. Our lab was one of the first to examine the clinical significance FLT3 mutations in AML. This work led to the acceptance of FLT3 internal tandem duplications (ITD) as being one of the most common and predictive prognostic factors for AML patients - especially those AML patients with normal cytogenetics. Subsequent studies from our lab have found that the biology and clinical significance of FLT3 mutations differ depending upon size, location, and other cooperative molecular events. Currently, our FLT3 research focuses on understanding the mechanism driving the heterogeneous molecular biology and clinical impact of FLT3 mutations in AML. These studies are using array platforms to examine expression differences of reference sequences and novel isoforms between the FLT3 mutations of varying sizes and allelic ratios. We are also prospectively examining the prognostic significance of the different types of FLT3 mutations in a large SWOG AML study.

2. Development of Novel AML Prognostic Biomarkers. AML is a relatively heterogeneous disease - even within specific cytogenetic and mutational subgroups, and there is a need for additional prognostic biomarkers to better risk-stratify AML patients. Many of these biomarkers may also be novel therapeutic targets. We have previously examined the differences in the global expression profiles between normal hematopoietic cells and AML blasts, identifying 13 genes with AML-specific expression changes. Many of these AML-specific expression changes had previously not been described (e.g., BIK). Subsequent analyses suggest that some of these genes may be prognostic factors and/or potential therapeutic targets. We are currently examining the prognostic significance of these genes in a large retrospective cohort of AML patients from SWOG. In addition, these studies found several of these 13 genes were primarily expressing novel splice variants in the AML blasts. This later finding suggests that alternative splicing may play a critical role in the molecular biology of AML and that all previous studies, including our own, probably miss many potentially critical AML-specific expression changes. Thus, we have developed methods to examining alternative splicing in AML using exon arrays.

3. Understand the Role of Aging in the Development of Hematopoietic Malignancies. As with most malignancies, the incidence of myeloid malignancies (AML, CML, MDS) increases with age, and as such, a better understanding of the molecular biology of the aging hematopoietic system may provide insight into hematopoietic transformation. Given the results from our preliminary studies, we are expanding our aging studies to include a larger cohort of normal and malignant samples and to examine an even broader spectrum of expression changes (e.g., proteomics, alternative splicing, microRNA). IRF8 displayed one of the most robust age-related expression changes in murine and human hematopoietic stem cells, and our studies and others suggest that these age-related changes may inhibit apoptosis, block differentiation, and even promote myeloid transformation. Furthermore, our initial studies suggest that IRF8 expression may also be associated with prognosis for AML and MDS, and thus, we are examining its prognostic significance in a large cohort of AML and MDS patients. We also are aggressively examining the underlying mechanism of the age- and malignant-related expression changes for IRF8 and how we may be able to reverse these changes. For example, we have found that methylation of the IRF8 promoter may be suppressing its expression in some hematopoietic malignancies and demethylating agents can restore its expression in a subset of these cells.

4. The Study of the Molecular Effects of DNA-damaging Agents on the Biology of Hematopoietic Cells and Malignant Transformation. Exposure to DNA-damaging agents is a major cause for secondary AML and MDS. As survivorship improves for many cancers, long-term secondary malignancies will become an increasing problem. In addition, there are growing concerns that large-scale accidental and premeditated exposures may place thousands of individuals at risk for secondary malignancies. Thus, we have expanded our studies to include investigations that examine the molecular biology of DNA-damaging agents and how this molecular biology may be useful in development of biomarkers to assess exposure, to predict disease, and to understand the process promoting transformation. We are currently focusing on radiation exposure due to its close link with secondary hematopoietic malignancies, wide use in the clinical arena, and high potential for large-scale accidental or premeditated exposures. These studies have identified a large number of genes with radiation induced expression changes in normal hematopoietic cells. These genes are being investigated as potential biomarkers for clinical biodosimetry assays, and studies are underway to determine if these expression changes persist after exposures in hematopoietic stem cells and may play a role in the development of secondary hematopoietic malignancies.

Memberships

American Society of Hematology

Honors and Awards

1999-2000, Hartwell Interdisciplinary Research Training Grant, Fred Hutchinson Cancer Research Center
1992, UNC Medical School Merit Award , University of North Carolina at Chapel Hill
1991, Alpha Omega Alpha, UNC Medical School, University of North Carolina at Chapel Hill
1987, Phi Beta Kappa, Davidson College

Previous Positions

2004-2009, Assistant Member, Fred Hutchinson Cancer Research Center, Clinical Research Division
2004-2009, Assistant Member, Fred Hutchinson Cancer Research Center, Clinical Research Division
2002-2004, Associate in Clinical Research, University of Washington, School of Medicine, Medicine, Oncology
1999-2002, Clinical Research Associate, University of Washington, School of Medicine, Medicine, Oncology
1996-1999, Fellow, University of Washington, School of Medicine, Medicine, Onocology
1995-1996, Chief Resident, University of North Carolina at Chapel Hill, School of Medicine, Medicine, Internal Medicine
1992-1995, Intern/Resident, University of North Carolina at Chapel Hill, School of Medicine, Medicine, Internal Medicine

Funding

  • National Institutes of Health (NIH): IRF8 as a Biomarker of Aging, Malignant Transformation, and AML Prognosis., $150,000/year, 2010 to 2011.
  • National Institutes of Health (NIH): CCEH P30 Pilot Award. Age-related Expression Changes in CD34+/38- Cells from Normal Donors, $20,000/year, 2005 to 2007.
  • National Institutes of Health (NIH): NIH NIAID U19 Project 3. Radiation Dose Dependent Interventions: Quantitative RT/PCR Based Radiation Dosimetry, $286,462/year, 2005 to 2010.
  • National Institutes of Health (NIH): NIH P20 Seattle Cancer and Aging Pilot Award. Surrogate Markers of Cancer Susceptibility in Older Patients, $115,654/year, 2003 to 2005.
  • National Institutes of Health (NIH): NIH K23 Career Development Award. An examination of FLT3 mutations in AML., $668,250/year, 2002 to 2007.
  • American Cancer Society (ACS): American Cancer Society Career Development Award. An Examination of FLT3 Mutations in AML, $150,000/year, 2002 to 2002.
  • National Institutes of Health (NIH): NIH K12 Career Development Award. The Clinical Significance of FLT3 Mutations in AML, $80,000/year, 1999 to 2000.

 

Recent Publications

2014
2013
2012
2011
2010
2009
2008