Derek Lynn Stirewalt
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.
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
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
Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report.. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 33(10):1157-64.. 2015.
Sample processing obscures cancer-specific alterations in leukemic transcriptomes.. Proceedings of the National Academy of Sciences of the United States of America. 111(47):16802-7.. 2014.
Hematopoietic stem cell transplantation for hematologic malignancies in older adults: geriatric principles in the transplant clinic.. Journal of the National Comprehensive Cancer Network : JNCCN. 12(1):128-36.. 2014.
Senior adult oncology, version 2.2014.. Journal of the National Comprehensive Cancer Network : JNCCN. 12(1):82-126.. 2014.
The Human Salivary Proteome is Radiation Responsive.. Radiation research.. 2014.
A model for prediction of FLT3-ITD and NPM1 (without FLT3-ITD) positivity in patients with newly diagnosed acute myeloid leukaemia.. British journal of haematology. 163(1):130-2.. 2013.
The prognostic significance of IRF8 transcripts in adult patients with acute myeloid leukemia.. PloS one. 8(8):e70812.. 2013.
Proteomic Classification of Acute Leukemias by Alignment-Based Quantitation of LC-MS/MS Data Sets.. Journal of proteome research. 11(10):5005-10.. 2012.
Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia.. British journal of haematology. 155(2):182-9.. 2011.
Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma.. Proceedings of the National Academy of Sciences of the United States of America. 108(12):5003-8.. 2011.
Blood-based detection of radiation exposure in humans based on novel phospho-Smc1 ELISA.. Radiation research. 175(3):266-81.. 2011.
Identification of radiation-induced expression changes in nonimmortalized human T cells.. Radiation research. 175(2):172-84.. 2011.
Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study.. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 24(5):909-13.. 2010.
Tumor necrosis factor polymorphism affects transplantation outcome in patients with myelodysplastic syndrome but not in those with chronic myelogenous leukemia, independent of the presence of HLA-DR15.. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 16(12):1700-6.. 2010.
Receptor tyrosine kinase alterations in AML - biology and therapy.. Cancer treatment and research. 145:85-108.. 2010.
Gene expression changes in normal haematopoietic cells.. Best practice & research. Clinical haematology. 22(2):249-69.. 2009.
Structural and numerical variation of FLT3/ITD in pediatric AML.. Blood. 111(10):4930-3.. 2008.