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Study Description

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 (GeneID:673), MAP2K1 (GeneID:5604), 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 developmental cellular origins, genomic, 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 study 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 and other receptor tyrosine kinase (RTK) inhibitors such as RET and ALK inhibitors that could potentially become effective therapy for these poorly understood blood cancers.

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Study Inclusion/Exclusion Criteria

The inclusion criteria involve any consented adult or pediatric patient (male or female) of any race or ethnicity with a diagnosed histiocytic or dendritic cell neoplasm of any subtype, classical hairy cell leukemia, or variant hairy cell leukemia who has pathological material [tissue, bone marrow, or blood (fresh, frozen, or formalin-fixed-paraffin-embedded (FFPE))] and paired normal blood or fingernails available for sequencing analysis. There are no exclusion criteria for this cohort study.

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Exome Sequencing Illumina HiSeq 2500 N/A N/A
Selected Publications
Diseases/Traits Related to Study (MeSH terms)
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Study Attribution
  • Principal Investigator
    • Omar Abdel-Wahab, MD. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Funding Source
    • R01 CA201247-01. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.