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Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures
Kevin Bielamowicz1,2, Peter Dimitrion3, Oussama Abla4
1Department of Pediatrics, College of Medicine at the University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Insights
Langerhans cell histiocytosis (LCH) is a neoplastic disorder driven by MAPK pathway mutations. Current therapies are insufficient for disseminated LCH, highlighting the need for targeted treatments.
Area of Science:
- Oncology
- Hematology
- Immunology
Background:
- Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder with diverse clinical presentations, ranging from localized lesions to life-threatening systemic disease.
- Current standard-of-care chemotherapy for disseminated LCH has limited efficacy, with fewer than 50% of patients achieving a cure and significant risk of long-term morbidity.
- Historically, the exact nature of LCH was debated, but recent discoveries have identified activating mitogen-activated protein kinase (MAPK) pathway mutations, such as BRAFV600E, in myeloid precursors as the drivers of lesion formation.
Purpose of the Study:
- To review the current understanding of LCH biology, clinical characteristics, and therapeutic strategies.
- To discuss the paradigm shift in understanding LCH as a clonal neoplastic disorder driven by specific mutations.
- To identify opportunities for improving patient outcomes through coordinated research and clinical trial efforts.
Main Methods:
- Review of seminal discoveries in LCH pathogenesis.
- Analysis of current therapeutic strategies and their limitations.
- Discussion of the translational gap between basic science discoveries and clinical trial development.
Main Results:
- LCH is now understood as a clonal neoplastic disorder driven by MAPK pathway mutations in myeloid precursors.
- Despite advances in understanding pathogenesis, current therapies for disseminated LCH remain suboptimal, with significant treatment failure rates.
- The insights into LCH biology offer promise for developing rational, mutation-targeted cures.
Conclusions:
- LCH is a neoplastic disorder, not merely a reactive condition, driven by specific genetic mutations.
- There is an urgent need to accelerate clinical trial development to translate recent biological discoveries into effective, targeted therapies for LCH.
- Coordinated efforts in agent prioritization and clinical trial design are crucial to improve outcomes for all LCH patients.
Abstract:
Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.
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