BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology

Abstract

Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNP) harboring activating somatic mutations in MAPK pathway genes, most notably BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPC) in multisystem LCH disease. How BRAFV600E mutation in HPC leads to LCH is not known. Here we show that enforced expression of the BRAFV600E mutation in early mouse and human multipotent HPC induced a senescence program that led to HPC growth arrest, apoptosis resistance and senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing towards the MNP lineage leading to the accumulation of senescent MNP in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice as well as pharmacologic blockade of SASP improved LCH disease in mice. These results identify senescent cells as a novel target for the treatment of LCH.

Rosai-Dorfman disease. A legacy of Professor Rosai that is still not exploited completely

“…p16 expression by large pale histiocytes of RDD could be considered as a senescence marker, like what has been demonstrated in ECD and LCH 35 , 36 , 43 , 44 . Activating mutations in the BRAF-MAPK pathway induces a senescence program (oncogene induced senescence, OIS), characterized by a reprogramming of mutated cells with a DNA damage response activation and a senescence-associated secretory phenotype – SASP –, affecting non-mutated bystander cells.…”

Development of BRAFV600E-positive acute myeloid leukemia in a patient on long-term dabrafenib for multisystem LCH

“…Interestingly, studies using mouse models of LCH demonstrate that BRAF V600E drives hematopoietic cell-cycle arrest and the accumulation of senescent mononuclear cells carrying the BRAF mutation. 14 In our patient, the contribution of MAPK pathway inhibition to malignant transformation of the BRAF clone is unknown in the setting of prior exposure to etoposide, cladribine, and clofarabine. However, it is evident in this case that MAPK pathway inhibition did not prevent the development of AML and may have contributed to or increased the risk for malignant transformation of persistent, senescent LCH cells.…”

<i>BRAF</i> V600E-positive cells as molecular markers of bone marrow disease in pediatric Langerhans cell histiocytosis

“…Langerhans cell histiocytosis (LCH) is an inflammatory myeloid hematologic malignancy in which genetic alterations in the MAPK pathway promote the differentiation of hematopoietic stem cells (HSC) into mononuclear phagocytic lineages such as monocytes and dendritic cells, resulting in apoptosis resistance, local inflammation, and impaired lymph node migration. 1-9 The BRAF V600E mutation is detected in various differentiation stages of myeloid cells, including HSC or nearby progenitors and mononuclear phagocytic cells, especially in high-risk systemic LCH. 1-9 Bone marrow (BM) involvement in LCH, which causes cytopenia, is characterized by CD1a-positive immunohistochemical staining.…”

“… 1-9 The BRAF V600E mutation is detected in various differentiation stages of myeloid cells, including HSC or nearby progenitors and mononuclear phagocytic cells, especially in high-risk systemic LCH. 1-9 Bone marrow (BM) involvement in LCH, which causes cytopenia, is characterized by CD1a-positive immunohistochemical staining. 10-15 However, the BRAF mutation status and clinical impact of BM disease (BMD) at the molecular level are not fully understood.…”

“…These results support the current theory of BRAF mutation acquisition in HSC or nearby progenitor cells in systemic LCH. 1-4 , 6 …”