While activating mutations of the serine-threonine kinase BRAF occur in ~8% of solid tumors, they are rare among hematopoietic malignancies except in hairy cell leukemia (HCL) and the systemic histiocytoses (SH) Langerhans Cell Histiocytosis and Erdheim-Chester Disease. The presence of the specific BRAFV600E mutation in nearly 100% of HCL and 40-60% of SH patients has provided major insights into our understanding of the pathophysiology of these poorly understood diseases. The development of targeted inhibitors of BRAF or its downstream mediators to treat solid tumors has led to major therapeutic advances, and more recently this paradigm has been applied in HCL and SH. Our interdisciplinary team has taken advantage of these advances in BRAFV600E mutation biology and therapeutics and recently published its findings tracing the origin of HCL to the hematopoietic stem cell and developed genetically accurate murine models of HCL. More recently, we have confirmed the presence of the BRAFV600E mutation in hematopoietic stem and progenitor cells in SH patients, generated mouse models of SH, identified recurrent mutations co-existing with the BRAFV600E mutation in both HCL and SH, and completed clinical trials of vemurafenib for HCL and SH patients. Although our preliminary data provide substantial evidence that HSPCs contribute to disease pathogenesis in both HCL and SH through their acquisition of BRAFV600E mutations, it is not yet clear how this common mutation drives the development of such phenotypically and clinically distinct disorders. Moreover, although we have noted that HCL and SH patients exhibit remarkable clinical responses to vemurafenib, we have begun to identify genetic mechanisms of vemurafenib resistance in HCL, which provides us with the unique opportunity to develop the next line of therapeutic strategies in the treatment of these disorders. Thus, the overall goal of this proposal is to delineate the cellular and functional requirements for HCL and SH pathogenesis and to utilize this information to identify the origins of resistance mutations that arise in the context of BRAF targeted therapy. We hypothesize that the cell in which the BRAFV600E mutant protein is active and/or the presence of collaborating mutations play a major role in determining disease phenotype and response to BRAF inhibition. We will address this hypothesis in the following Aims: 1) Delineate the functional effects of the BRAFV600E mutation on hematopoiesis based on the cell in which it is active, 2) Identify the constellation of mutations co-existing with the BRAFV600E mutation in HCL and SH, and 3) Identify the mechanisms of BRAF inhibitor resistance. This project will provide a comprehensive characterization of the cellular origins and cooperating mutations that give rise to HCL and SH. Moreover, this work will delineate mechanisms of BRAF inhibitor resistance in hematopoietic malignancies - an effort that may have broader benefits to the larger population of BRAF-mutant cancer patients ineffectively treated with current BRAF inhibitors.

Public Health Relevance

We recently demonstrated that the BRAFV600E mutation occurs in hematopoietic stem and progenitor cells (HSPCs) in patients with hairy cell leukemia and the systemic histiocytoses (SH), Langerhans Cell Histiocytosis and Erdheim-Chester Disease, but the mechanism by which a single gene contributes to distinct hematological diseases is not well-understood. We will characterize the mechanisms that drive the pathogenesis and therapeutic resistance in HCL and SH by defining differences in the pattern of BRAFV600E activation as well as cooperating mutations that occur in both HSPCs and lesional cells of these disorders, and utilizing mouse models to experimentally validate these findings. We expect our studies to elucidate mechanisms underlying the development of disparate hematologic malignancies driven by shared mutations, provide comprehensive description of the genetic events that co-exist with the BRAFV600E mutation to drive these disorders and RAF inhibitor resistance, and to develop tools to design novel therapeutic strategies to address RAF inhibitor resistance in these disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA201247-05
Application #
10007587
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Howcroft, Thomas K
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Bhatia, Ankush; Ulaner, Gary; Rampal, Raajit et al. (2018) Single-agent dabrafenib for BRAFV600E-mutated histiocytosis. Haematologica 103:e177-e180
Kaley, Thomas; Touat, Mehdi; Subbiah, Vivek et al. (2018) BRAF Inhibition in BRAFV600-Mutant Gliomas: Results From the VE-BASKET Study. J Clin Oncol :JCO2018789990
Diamond, Eli L; Subbiah, Vivek; Lockhart, A Craig et al. (2018) Vemurafenib for BRAF V600-Mutant Erdheim-Chester Disease and Langerhans Cell Histiocytosis: Analysis of Data From the Histology-Independent, Phase 2, Open-label VE-BASKET Study. JAMA Oncol 4:384-388
Zarnegar, Sara; Durham, Benjamin H; Khattar, Pallavi et al. (2018) Novel activating BRAF fusion identifies a recurrent alternative mechanism for ERK activation in pediatric Langerhans cell histiocytosis. Pediatr Blood Cancer 65:
Papo, Matthias; Diamond, Eli L; Cohen-Aubart, Fleur et al. (2017) High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis. Blood 130:1007-1013
Durham, Benjamin H; Roos-Weil, Damien; Baillou, Claude et al. (2017) Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells. Blood 130:176-180
Durham, Benjamin H; Getta, Bartlomiej; Dietrich, Sascha et al. (2017) Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations. Blood 130:1644-1648
Ozkaya, Neval; Dogan, Ahmet; Abdel-Wahab, Omar (2017) Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms. Hematol Oncol Clin North Am 31:705-719
Mass, Elvira; Jacome-Galarza, Christian E; Blank, Thomas et al. (2017) A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549:389-393
Milne, Paul; Bigley, Venetia; Bacon, Chris M et al. (2017) Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-Chester disease in adults. Blood 130:167-175

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