Research: Hairy cell leukemia (HCL) and the systemic histiocytoses (SH) are unique amongst hematopoietic malignancies in that they both harbor a high frequency of mutations in BRAFV600E and MAP2K1. Although these disorders share common molecular alterations, HCL and the SH have very distinct clinical behavior and are suspected to have different lineage derivations. However, the precise biological basis for the differences in their pathogenesis is poorly understood. In addition, the molecular pathogenesis and therapeutic responsiveness of non-BRAFV600E-mutated variant HCL (vHCL) and SH to mitogen activated protein kinase (MAPK) pathway inhibitors are also undefined. Finally, the genetic mechanisms for RAF inhibitor resistance recently described clinically in classic HCL (cHCL) patients are unknown. Thus, the primary goal of this project is to determine how BRAFV600E, MAP2K1, and other kinase alterations contribute to the pathogenesis of distinct hematopoietic disorders and affect their clinical responses to MAPK pathway inhibitors. This proposal will utilize banked HCL and SH patient samples and several newly developed in vitro and in vivo murine models to pursue this goal. We expect these studies to establish a paradigm for understanding the pathogenesis of genetically related disorders arising in the same tissue system by incorporating both genetic and developmental biology perspectives, as well as providing new biological and therapeutic insights into MAPK-driven hematopoietic neoplasms. Candidate: Dr. Benjamin Durham is a hematopathologist and molecular genetic pathologist who currently serves as a Genomic Pathology Research Fellow in the Department of Pathology at MSKCC.
He aims to become an independent, tenure-track physician-scientist investigating the molecular pathogenesis of hematological malignancies through a combination of genomics, functional genomics, and murine modeling. Dr. Durham has outlined a five-year period of mentored training to strengthen his skills in functional genomics and disease modeling. This training period will be carried out under the mentorship of Dr. Omar Abdel-Wahab, a rising leader in the functional genomics of hematopoietic malignancies and Dr. Neal Rosen, an expert in MAPK and PI3K-AKT signaling. Dr. Durham has also assembled an advisory committee composed of Drs. Charles Sawyers, James Fagin, Frdric Geissmann, Marc Ladanyi, and Christopher Park who will help guide his training and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting more than 130 years to exceptional patient care, innovative research, and outstanding educational programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent physician-scientists.
The Mitogen-Activated Protein Kinase (MAPK) signaling pathway has been critically important in understanding pathology and developing targeted therapy for many cancers, but high frequency mutations in this pathway in hematopoietic malignancies were unknown until a series of sequencing studies from our group and others revealed a high frequency of activating mutations in BRAF, MAP2K1, and other key components of the MAPK pathway in two groups of rare and poorly studied blood cancers: hairy cell leukemia (HCL) and the systemic histiocytoses (SH). Although HCL and the SH both share common gene mutations in BRAF (BRAFV600E) and MAP2K1, these are distinct blood cancers with different clinical behaviors; however, their actual cells of origin and pathogenic differences are poorly understood, which led to our project goal of determining how BRAFV600E, MAP2K1, and other MAPK pathway mutations contribute to the pathogenesis of distinct blood cancers and affect their clinical responses to MAPK pathway inhibitors. This research proposal seeks to advance our understanding of the actual cells of origin of cancer-causing MAPK mutations in HCL and the SH, to determine why BRAFV600E and MAP2K1 mutations can cause two distinct blood cancers, and to understand how these mutations in HCL and SH influence responses to MAPK pathway inhibitor drugs that could potentially become effective therapy for these poorly understood blood cancers.