Possible Myeloid Progenitor Cells Involved in Langerhans Cell Histiocytosis

A research team has identified a progenitor population of cells that may serve as a carrier of mutations involved in the development of both high-risk and low-risk Langerhans cell histiocytosis (LCH). These findings were reported in Blood.

The investigators explained that LCH is associated with activating mutations involved in the mitogen-activated protein kinase (MAPK) pathway. According to the researchers, LCH generally exists as either a high-risk, multisystem form that appears to arise from the bone marrow or as a low-risk, single-system (SS) form that may emerge from circulating or tissue-specific cells.

The research team hypothesized, based on prior research, that the Lin^–CD34⁺c-Kit⁺Flt3⁺ myeloid progenitor population may possess a driver mutation, such as a BRAF variant, associated with LCH in both high-risk and low-risk patient groups.

In their analysis, samples were obtained from blood, bone marrow, and/or from LCH lesions from patients with LCH. Blood and bone marrow samples were also obtained from hematopoietic stem cell donors. A total of 27 samples were analyzed from patients with LCH, and 43 samples were analyzed from donors.

Cells were isolated through flow cytometry or immunohistochemistry. Next-generation sequencing or droplet digital polymerase chain reaction was performed for detection of BRAF^V600E, BRAF^V600D, or BRAF^WT sequences. The researchers also cultured and aimed to differentiate Lin^–CD34⁺c-Kit⁺Flt⁺ cells into dendritic cell (DC) or Langerhans cell (LC)-like groups.

Samples from both high-risk and low-risk patients showed elevated levels of CD34⁺c-Kit⁺Flt3⁺ cells compared with tissue from donors. These cells originating from both high-risk and low-risk patients were able to serve as progenitors of both DC and LC-like populations, and BRAF mutations were detected across multiple myeloid cell types in LCH lesions of low-risk patients.

“The presence of mutated progenitor cells in lesions of SS LCH patients and mutated myeloid cells in both blood and lesions of low-risk LCH patients (our data) suggest that the mechanism underlying low-risk and high-risk LCH pathogenesis may be the same,” the researchers wrote.

One clinical implication that the researchers identified was that localized treatment given to patients with a single LCH lesion may be insufficient, and that systemic therapy may be required.

Reference

Xiao Y, van Halteren A, Lei X, et al. Bone marrow-derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis. Blood. Published online August 4, 2020. doi:10.1182/blood.2020005209