# Origins of BRAF-mutant hematologic malignancies and their therapeutic resistance

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $536,090

## Abstract

Summary
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 popul...

## Key facts

- **NIH application ID:** 10007587
- **Project number:** 5R01CA201247-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Omar Abdel-Wahab
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,090
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007587

## Citation

> US National Institutes of Health, RePORTER application 10007587, Origins of BRAF-mutant hematologic malignancies and their therapeutic resistance (5R01CA201247-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10007587. Licensed CC0.

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