CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions

Kenneth L. McClain, Jennifer Picarsic, Rikhia Chakraborty, Daniel Zinn, Howard Lin, Harshal Abhyankar, Brooks Scull, Albert Shih, Karen Phaik Har Lim, Olive Eckstein, Joseph Lubega, Tricia L. Peters, Walter Olea, Thomas Burke, Nabil Ahmed, M. John Hicks, Brandon Tran, Jeremy Jones, Robert Dauser, Michael JengRobert Baiocchi, Deborah Schiff, Stanton Goldman, Kenneth M. Heym, Harry Wilson, Benjamin Carcamo, Ashish Kumar, Carlos Rodriguez-Galindo, Nicholas S. Whipple, Patrick Campbell, Geoffrey Murdoch, Julia Kofler, Simon Heales, Marian Malone, Randall (Randy) Woltjer, Joseph Quinn, Paul Orchard, Michael C. Kruer, Ronald Jaffe, Markus G. Manz, Sergio A. Lira, D. Williams Parsons, Miriam Merad, Tsz Kwong Man, Carl E. Allen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+CD33+CD163+P2RY12-) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20.

Original languageEnglish (US)
Pages (from-to)2607-2620
Number of pages14
JournalCancer
Volume124
Issue number12
DOIs
StatePublished - Jun 15 2018

Fingerprint

Langerhans Cell Histiocytosis
Central Nervous System
Brain
Cerebrospinal Fluid Proteins
Cerebrospinal Fluid
Osteopontin
Biopsy
DNA
Myeloid Cells
Brain Neoplasms
Neurodegenerative Diseases
Monocytes
Blood Cells
Biomarkers
Pathology
Phenotype

Keywords

  • BRAF-V600E
  • CNS neoplasms
  • Langerhans cell histiocytosis
  • neurodegeneration
  • osteopontin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

McClain, K. L., Picarsic, J., Chakraborty, R., Zinn, D., Lin, H., Abhyankar, H., ... Allen, C. E. (2018). CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer, 124(12), 2607-2620. https://doi.org/10.1002/cncr.31348

CNS Langerhans cell histiocytosis : Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. / McClain, Kenneth L.; Picarsic, Jennifer; Chakraborty, Rikhia; Zinn, Daniel; Lin, Howard; Abhyankar, Harshal; Scull, Brooks; Shih, Albert; Lim, Karen Phaik Har; Eckstein, Olive; Lubega, Joseph; Peters, Tricia L.; Olea, Walter; Burke, Thomas; Ahmed, Nabil; Hicks, M. John; Tran, Brandon; Jones, Jeremy; Dauser, Robert; Jeng, Michael; Baiocchi, Robert; Schiff, Deborah; Goldman, Stanton; Heym, Kenneth M.; Wilson, Harry; Carcamo, Benjamin; Kumar, Ashish; Rodriguez-Galindo, Carlos; Whipple, Nicholas S.; Campbell, Patrick; Murdoch, Geoffrey; Kofler, Julia; Heales, Simon; Malone, Marian; Woltjer, Randall (Randy); Quinn, Joseph; Orchard, Paul; Kruer, Michael C.; Jaffe, Ronald; Manz, Markus G.; Lira, Sergio A.; Parsons, D. Williams; Merad, Miriam; Man, Tsz Kwong; Allen, Carl E.

In: Cancer, Vol. 124, No. 12, 15.06.2018, p. 2607-2620.

Research output: Contribution to journalArticle

McClain, KL, Picarsic, J, Chakraborty, R, Zinn, D, Lin, H, Abhyankar, H, Scull, B, Shih, A, Lim, KPH, Eckstein, O, Lubega, J, Peters, TL, Olea, W, Burke, T, Ahmed, N, Hicks, MJ, Tran, B, Jones, J, Dauser, R, Jeng, M, Baiocchi, R, Schiff, D, Goldman, S, Heym, KM, Wilson, H, Carcamo, B, Kumar, A, Rodriguez-Galindo, C, Whipple, NS, Campbell, P, Murdoch, G, Kofler, J, Heales, S, Malone, M, Woltjer, RR, Quinn, J, Orchard, P, Kruer, MC, Jaffe, R, Manz, MG, Lira, SA, Parsons, DW, Merad, M, Man, TK & Allen, CE 2018, 'CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions', Cancer, vol. 124, no. 12, pp. 2607-2620. https://doi.org/10.1002/cncr.31348
McClain KL, Picarsic J, Chakraborty R, Zinn D, Lin H, Abhyankar H et al. CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer. 2018 Jun 15;124(12):2607-2620. https://doi.org/10.1002/cncr.31348
McClain, Kenneth L. ; Picarsic, Jennifer ; Chakraborty, Rikhia ; Zinn, Daniel ; Lin, Howard ; Abhyankar, Harshal ; Scull, Brooks ; Shih, Albert ; Lim, Karen Phaik Har ; Eckstein, Olive ; Lubega, Joseph ; Peters, Tricia L. ; Olea, Walter ; Burke, Thomas ; Ahmed, Nabil ; Hicks, M. John ; Tran, Brandon ; Jones, Jeremy ; Dauser, Robert ; Jeng, Michael ; Baiocchi, Robert ; Schiff, Deborah ; Goldman, Stanton ; Heym, Kenneth M. ; Wilson, Harry ; Carcamo, Benjamin ; Kumar, Ashish ; Rodriguez-Galindo, Carlos ; Whipple, Nicholas S. ; Campbell, Patrick ; Murdoch, Geoffrey ; Kofler, Julia ; Heales, Simon ; Malone, Marian ; Woltjer, Randall (Randy) ; Quinn, Joseph ; Orchard, Paul ; Kruer, Michael C. ; Jaffe, Ronald ; Manz, Markus G. ; Lira, Sergio A. ; Parsons, D. Williams ; Merad, Miriam ; Man, Tsz Kwong ; Allen, Carl E. / CNS Langerhans cell histiocytosis : Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. In: Cancer. 2018 ; Vol. 124, No. 12. pp. 2607-2620.
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abstract = "BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10{\%}) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+CD33+CD163+P2RY12-) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20.",
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TY - JOUR

T1 - CNS Langerhans cell histiocytosis

T2 - Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions

AU - McClain, Kenneth L.

AU - Picarsic, Jennifer

AU - Chakraborty, Rikhia

AU - Zinn, Daniel

AU - Lin, Howard

AU - Abhyankar, Harshal

AU - Scull, Brooks

AU - Shih, Albert

AU - Lim, Karen Phaik Har

AU - Eckstein, Olive

AU - Lubega, Joseph

AU - Peters, Tricia L.

AU - Olea, Walter

AU - Burke, Thomas

AU - Ahmed, Nabil

AU - Hicks, M. John

AU - Tran, Brandon

AU - Jones, Jeremy

AU - Dauser, Robert

AU - Jeng, Michael

AU - Baiocchi, Robert

AU - Schiff, Deborah

AU - Goldman, Stanton

AU - Heym, Kenneth M.

AU - Wilson, Harry

AU - Carcamo, Benjamin

AU - Kumar, Ashish

AU - Rodriguez-Galindo, Carlos

AU - Whipple, Nicholas S.

AU - Campbell, Patrick

AU - Murdoch, Geoffrey

AU - Kofler, Julia

AU - Heales, Simon

AU - Malone, Marian

AU - Woltjer, Randall (Randy)

AU - Quinn, Joseph

AU - Orchard, Paul

AU - Kruer, Michael C.

AU - Jaffe, Ronald

AU - Manz, Markus G.

AU - Lira, Sergio A.

AU - Parsons, D. Williams

AU - Merad, Miriam

AU - Man, Tsz Kwong

AU - Allen, Carl E.

PY - 2018/6/15

Y1 - 2018/6/15

N2 - BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+CD33+CD163+P2RY12-) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20.

AB - BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+CD33+CD163+P2RY12-) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20.

KW - BRAF-V600E

KW - CNS neoplasms

KW - Langerhans cell histiocytosis

KW - neurodegeneration

KW - osteopontin

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