Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes

Lee, Lynn; Gasilina, Anjelika; Roychoudhury, Jayeeta; Clark, Jason; McCormack, Francis X.; Pressey, Joseph G.; Grimley, Michael; Lorsbach, Robert B.; Ali, Siraj M.; Bailey, Mark; Stephens, Philip J.; Ross, Jeffrey S.; Miller, Vincent A.; Nassar, Nicolas; Kumar, Ashish

doi:10.1172/jci.insight.89473

Cited by 73 publications

(79 citation statements)

References 43 publications

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“…KIF5B-ALK fusions, therefore, result in inappropriate ALK expression and constitutive activation of the MAPK and PI3K-AKT pathways within histiocytes. Similarly, an EML4-ALK rearrangement was also more recently described in the lesional biopsy of an adolescent patient with histiocytosis not otherwise specified (NOS) [30]. Both the KIF5B-ALK and EML4-ALK fusions have similar configurations to those previously described in non-small-cell lung cancer [31, 32] and are functionally activating kinase fusions that show sensitivity to ALK inhibition in vitro .…”

Section: Gene Fusionsmentioning

confidence: 54%

“…These findings emphasize the importance of functional assessment of genomic data in assigning treatment for patients. In another recent study, an adult LCH patient with FDG-PET lesions in the neck and groin declined systemic chemotherapy owing to concerns regarding its impact on her quality of life [30]. Targeted sequencing of a biopsy from the neck lesion revealed a BRAF inframe-deletion (N486_P490del) with a VAF of 14%.…”

Section: Therapeutic Efficacy Of Kinase Inhibitor Therapy In Histiocymentioning

confidence: 99%

“…Thus, trametinib was started and within 5 days of initiating treatment, her neck and groin tumors disappeared. Follow-up PET-CT showed her lesions had completely resolved [30]. …”

Section: Therapeutic Efficacy Of Kinase Inhibitor Therapy In Histiocymentioning

confidence: 99%

See 2 more Smart Citations

Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms

Özkaya

Doğan

Abdel‐Wahab

2017

Hematology/Oncology Clinics of North America

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Section: Gene Fusionsmentioning

confidence: 54%

Section: Therapeutic Efficacy Of Kinase Inhibitor Therapy In Histiocymentioning

confidence: 99%

See 1 more Smart Citation

Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms

Özkaya

Doğan

Abdel‐Wahab

2017

Hematology/Oncology Clinics of North America

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“…Approximately half of ECD patients harbor BRAF ‐V600E as well as LCH, and ~30% carry MAP2K1 mutations. Whereas 10%‐20% of ECD are positive for NRAS or KRAS mutations, only one activating KRAS mutation in non‐PLCH has been reported to date . The effects of these recently identified mutations on ERK activation are still unclear.…”

Section: Alterations Of the Mapk Pathway In Lchmentioning

confidence: 99%

Langerhans cell histiocytosis in adults: Advances in pathophysiology and treatment

2018

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Langerhans cell histiocytosis (LCH) is a rare systemic disorder characterized by the accumulation of CD1a+/Langerin+ LCH cells and wide‐ranging organ involvement. Langerhans cell histiocytosis was formerly referred to as histiocytosis X, until it was renamed in 1987. Langerhans cell histiocytosis β was named for its morphological similarity to skin Langerhans cells. Studies have shown that LCH cells originate from myeloid dendritic cells rather than skin Langerhans cells. There has been significant debate regarding whether LCH should be defined as an immune disorder or a neoplasm. A breakthrough in understanding the pathogenesis of LCH occurred in 2010 when a gain‐of‐function mutation in BRAF (V600E) was identified in more than half of LCH patient samples. Studies have since reported that 100% of LCH cases show ERK phosphorylation, indicating that LCH is likely to be a clonally expanding myeloid neoplasm. Langerhans cell histiocytosis is now defined as an inflammatory myeloid neoplasm in the revised 2016 Histiocyte Society classification. Randomized trials and novel approaches have led to improved outcomes for pediatric patients, but no well‐defined treatments for adult patients have been developed to date. Although LCH is not fatal in all cases, delayed diagnosis or treatment can result in serious impairment of organ function and decreased quality of life. This study summarizes recent advances in the pathophysiology and treatment of adult LCH, to raise awareness of this “orphan disease”.

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“…In vitro functional studies show that the MEK inhibitor U0126 can inhibit ERK activation resulting from these mutations in this region of MAP2K1 . Another study showed that the p.F53_Q58 > L, p.Q58_E62del, and p.C121S/G128V mutations in MAP2K1 constituently activated ERK and were susceptible in vitro to MEK inhibitors including trametinib . Interestingly, a recent report describes the complete remission of an LCH patient with an MAP2K1 p.E102‐I103del mutation treated with trametinib .…”

Section: Resultsmentioning

confidence: 99%

Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis

Azorsa

Lee

Wai

et al. 2018

Pediatric Blood & Cancer

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Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance.

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Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes

Cited by 73 publications

References 43 publications

Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms

Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms

Langerhans cell histiocytosis in adults: Advances in pathophysiology and treatment

Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis

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