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Progress in understanding the pathogenesis of Langerhans : back to Histiocytosis X?

Marie-Luise Berres,1,2,3,4 Miriam Merad1,2,3 and Carl E. Allen5,6

1Department of Oncological Sciences, Mount Sinai School of Medicine, 2Tisch Cancer Institute, Mount Sinai School of Medicine, 3Immunology Institute, Mount Sinai School of Medicine, New York, NY, USA, 4Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany, 5Texas Children’s Cancer Center, and 6Baylor College of Medicine, Houston, TX, USA

Summary histiocytosis (LCH) is the most common his- tiocytic disorder, arising in approximately five children per Langerhans cell histiocytosis (LCH), the most common million, similar in frequency to paediatric Hodgkin lym- histiocytic disorder, is characterized by the accumulation of phoma and acute myeloid leukaemia (AML) (Guyot-Goubin CD1A+/CD207+ mononuclear within - et al, 2008; Stalemark et al, 2008; Salotti et al, 2009). The tous lesions that can affect nearly all organ systems. Histori- median age of presentation is 30 months, though LCH is cally, LCH has been presumed to arise from transformed or reported in adults in approximately one adult per million, pathologically activated epidermal dendritic cells called Lan- both as unrecognized chronic paediatric disease and de novo gerhans cells. However, new evidence supports a model in disease (Baumgartner et al, 1997). There are occasional which LCH occurs as a consequence of a misguided differen- reports of affected non-twin siblings and multiple cases in tiation programme of myeloid precursors. one family, though it is not clear if this is significantly more Genetic, molecular and functional data implicate activation frequent than one would expect by chance (Arico et al, of the ERK signalling pathway at critical stages in myeloid 2005). differentiation as an essential and universal driver of LCH The clinical presentations of LCH vary from clinically triv- pathology. Based on these findings, we propose that LCH ial lesions that resolve spontaneously or with curettage to should be re-defined as an inflammatory myeloid neoplasia. life-threatening disseminated disease that requires systemic Increased understanding of LCH pathogenesis will provide chemotherapy and, in some cases, haematopoietic opportunities to optimize and personalize therapy through transplantation. The wide spectrum of clinical manifestations improved risk-stratification, targeted therapy and assessment that overlap with more common paediatric conditions make of therapy response based on specific molecular features and diagnosis of LCH challenging. In an institutional study, we origin of the pathological myeloid cells. found that the time from clinical symptoms of LCH lesions to diagnostic biopsy was a median of 3 months, and Keywords: Langerhans cell histiocytosis, BRAF V600E, extra- in some cases diagnosis was delayed by over 5 years (Simko cellular signal-regulated kinase signalling pathway, misguided et al, 2014a). However, once biopsy is performed, diagnosis myeloid differentiation, inflammatory myeloid neoplasia. of LCH is straightforward: LCH is defined by CD1A+/ CD207+ with an inflammatory background, including variable numbers of (enriched for reg- Clinical overview ulatory T cells), and (Favara et al, 1997; Chikwava & Jaffe, 2004; Senechal et al, 2007). Histiocytic disorders include diseases involving aberrant Traditionally, therapy for patients with LCH is determined ‘histiocytes’. While translates to ‘tissue cell’, histio- by the extent and location of the lesions. The optimal thera- cytic disorders include all diseases associated with cells of the peutic approaches for LCH remain incompletely defined as mononuclear system, which is comprised of hae- patients with skin-limited lesions, single- lesions and matopoietic cells with mononuclear morphology and phago- isolated diabetes insipidus have not been studied on prospec- cytic activity (van Furth & Cohn, 1968; Favara et al, 1997). tive clinical trials. Standard of care for LCH has evolved from serial clinical trials based on empirically-derived therapeutic strategies. Patients with liver, and/or Correspondence: Marie-Luise Berres, Department of Internal involvement are at highest risk for mortality. In the most Medicine III, University Hospital of Aachen, RWTH Aachen, recent Histiocyte Society trial, LCHIII, 5-year overall survival Pauwelstrasse 30, Aachen 52074, Germany. for patients with risk-organ disease was 84%, compared to E-mail: [email protected] 99% for patients without risk-organ disease (Gadner et al,

ª 2014 John Wiley & Sons Ltd First published online 28 November 2014 British Journal of Haematology, 2015, 169, 3–13 doi: 10.1111/bjh.13247 Review

2013). The current standard of care, based on LCHIII, is the duration of active, uncontrolled disease (Willis et al, 1 year of therapy with vinblastine and prednisone, plus mer- 1996; Haupt et al, 2013). Complications include endocrinop- captopurine for patients with high-risk disease. Response to athies (posterior and anterior pituitary), neurodegenerative initial therapy is also an important prognostic factor for syndrome, decreased pulmonary function, orthopaedic patients with high-risk LCH: Survival was 95% for patients problems and liver failure due to progressive sclerosing cho- with good response after the first 6 weeks of treatment on langitis. LCHIII, 83% for patients with intermediate response and 57% for patients who progressed on therapy (Gadner et al, Historical concepts of LCH pathogenesis 2013). (1900s–2010) Langerhans cell histiocytosis may involve the central ner- vous system (CNS) with mass lesions (brain tumours), pitui- Langerhans cell histiocytosis has suffered from several histori- tary lesions resulting in diabetes insipidus (DI) and/or a cal identity crises, many of which persist today. We hypothe- neurodegenerative syndrome. A large international series size that difficulty in defining the biology of LCH relative to observed that risk of development of DI was decreased in other neoplastic disorders has left it (and patients with LCH) patients with bone lesions in mastoid, temporal, orbital and on the sidelines of scientific and haematology/oncology clini- skull base who received systemic chemotherapy (Grois et al, cal research cooperative group agendas. 2006). Therefore, systemic therapy is now considered stan- dard of care for patients with ‘CNS risk’ skull and pituitary Evolution of the LCH brand lesions. A devastating consequence of LCH is development of a progressive CNS neurodegenerative syndrome that may The first reports of patients now recognized as having LCH were develop years after the apparent resolution of LCH (Grois reported in the early 1900s, describing children with bone et al, 2010). Reports of treatment for the CNS neurodegener- lesions, mucosal lesions and diabetes insipidus (Hand-Schuller-€ ative syndrome have been limited to case series and pilot Christian disease) or infants with hepatosplenomegaly and his- studies, and include corticosteroids, cladribine, all-trans reti- tiocytic infiltration of the bone marrow (Letterer-Siwe disease) noic acid, intravenous immunogobulin and cytarabine (Arceci, 1999). Hashimoto-Pritzker syndrome describes sponta- (Idbaih et al, 2004; Dhall et al, 2008; Imashuku et al, 2008; neously-resolving skin lesions in infants (Hashimoto & Pritzker, Allen et al, 2010a). 1973). ‘Eosinophilic granuloma’ is also a frequently used While mortality in patients with high-risk LCH is improv- nomenclature for bone LCH. Despite the spectrum of clinical ing, and survival is near universal in patients with low-risk presentations, the histological appearance of an LCH lesion is LCH, ‘reactivation’ (a term for relapse intended to remain relatively consistent. In 1953, Dr. Lichtenstein proposed that the neutral on LCH as immune versus a malignant disorder) various clinical conditions with the shared histopathology prob- remains a significant problem. Over half of all patients are ably represent a common condition, which he proposed to be refractory to vinblastine/prednisone or develop recurrent collectively named ‘Histiocytosis X’, with the ‘X’ as an indica- lesions (Minkov et al, 2008; Gadner et al, 2013). Optimal tion of incomplete understanding of the cell of origin (Lichten- ‘salvage’ strategies have not been defined. In a prospective stein, 1953). Twenty years later, the Birbeck granule, a Histiocyte Society trial, cladribine (5 mg/m2 daily 9 5 days cytoplasmic structure associated with (CD207), per month) had high response rates, but rarely resulted in thought to have some function in processing, was dis- cure in a prospective trial (Weitzman et al, 2009). A much covered by electron microscopy in the pathological mononu- more intense strategy with cladribine (9 mg/m2) and cytara- clear phagocytic cells of LCH lesions. As epidermal Langerhans bine (1 g/m2 daily 9 5 days per month) was tested in a cells (LCs) were the only cells at that time known to contain Bir- small trial and resulted in a high rate of cure, but also a very beck granules, ‘Histiocytosis X’ was hypothesized to arise from high rate of treatment-related mortality (Bernard et al, epidermal LCs, and has since been rebranded as ‘Langerhans cell 2005). Clinical series suggest that clofarabine, when dosed histiocytosis’ (Nezelof et al, 1973). For the next four decades, ~50% below the maximum tolerated dose, used in AML and models of LCH were primarily based on the assumption that other paediatric malignancies (25–52 mg/m2/day 9 5 days LCH arises from epidermal LC, with the ongoing question: Does per month) may be effective with modest toxicity in patients LCH arise from a pathological activation or neoplastic transfor- with disease refractory to other salvage regiments (Rodri- mation of the epidermal LC? guez-Galindo et al, 2008; Abraham et al, 2013; Simko et al, 2014b). This efficacy might further be improved by higher Inflammation/immune dysregulation in LCH doses of clofarabine in refractory cases, but clinical experi- ences are limited to single cases (Simko et al, 2014b). Langerhans cell histiocytosis lesions have a median of only Permanent consequences and late effects of disease as well 8% pathological ‘LCs’ (Berres et al, 2014). The remainder of as therapy remain significant challenges, arising in the major- the lesion is composed of a diverse inflammatory infiltrate. ity of patients with LCH. The risk of developing complica- The impressively inflammatory character of LCH lesions led tions is related to extent of disease at presentation as well as to the investigation of and immune dysregulation

4 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 3–13 Review as mechanisms of pathogenesis. Many viruses have been Redefining LCH in the molecular era hypothesized to play roles in LCH pathogenesis, but none have been convincingly validated (Jeziorski et al, 2008). Most Somatic gene mutations/MAPK activation in LCH recently, an association with the relatively ubiquitous Merc- Analysis of genomic alterations in LCH had traditionally kel cell polyomavirus and LCH has been reported (Murakami been challenging due to the cellular heterogeneity of the et al, 2014), however the significance of this observation lesions. The progress in sequencing technology amplifying remains uncertain. the depth of sequencing coverage by next-generation Immunologically, the lesional cells share some features with sequencing techniques recently allowed the identification of a resting epidermal LCs, including high levels of CD207+ and recurrent somatic mutation in the gene encoding for the pro- CD1A+ expression, but also possess features of activated LCs, tein kinase BRAF (Badalian-Very et al, 2010). The high prev- including expression of T cell co-stimulatory molecules and alence of the BRAF V600E point mutation in LCH has been pro-inflammatory cytokines, creating a ‘cytokine storm’ (Gei- validated in several independent cohorts and attributed to ssmann et al,2001;Lamanet al, 2003; Allen et al,2010b). the histiocytes within the lesions (Haroche et al, 2012; Sahm Interestingly, CD4+ CD25+ CTLA4+ regulatory T cells are et al, 2012; Satoh et al, 2012; Berres et al, 2014). A recent enriched in LCH lesions, and patients with LCH may have meta review comprising 653 patient samples assessed an impaired skin delayed-type hypersensitivity responses (Sene- overall frequency of 485% for the BRAF V600E point muta- chal et al, 2007; Allen et al, 2010b). Moreover, a causal role tion in LCH (Bubolz et al, 2014). However, we speculate the for LCH pathogenesis from elevated IL17a expression by LCH actual frequency is higher as methods other than quantitative cells has also been proposed, but these results have not been polymerase chain reaction may be insufficiently sensitive to confirmed by other groups (Coury et al, 2008; Allen & identify BRAF V600E in cases of lesions with sparse infiltra- McClain, 2009; Peters et al, 2011; Makras et al, 2012). tion by pathological LCH cells. Despite the inflammatory character of LCH lesions, infec- BRAF is a central kinase of the RAS/RAF/MEK pathway, tious or autoimmune causes for LCH pathogenesis remain to which is essentially involved in numerous cell functions be proven. Furthermore, the contributions of inflammation including cell proliferation and migration and is frequently to clinical manifestations of LCH remain to be defined. mutated in various cancer cells (Davies et al, 2002). The BRAF V600E mutation results in a constitutive, RAS-inde- LCH as a neoplastic disorder pendent activation of the downstream kinases extracellular signal-regulated kinase (ERK) and mitogen-activated protein The alternative model to LCH pathogenesis caused by dys- kinase (MAPK)/ERK kinase (MEK) (Maurer et al, 2011). Of functional immune activation has traditionally been neoplastic note, both downstream kinases are highly activated in LCH transformation of epidermal LCs (Nezelof et al, 1973). Langer- cells with BRAF V600E mutation, supporting the potential hans cell histiocytosis lesions do have many classical features functional relevance of the mutation in LCH (Badalian-Very of malignancy (Hanahan & Weinberg, 2011). Based on non- et al, 2010; Chakraborty et al, 2014). Interestingly, ERK sig- random X-inactivation, the CD1A+ cells of LCH lesions were nalling has been highly implicated in myeloid cell differentia- determined to be clonal (Willman et al,1994;Yuet al,1994). tion and maturation under physiological conditions. While Moreover, lesions display malignancy-associated mechanisms, hyperphosphorylation of ERK drives differentiation of den- e.g., immune evasion with enriched regulatory T cell popula- dritic cell (DC) progenitors (Miranda et al, 2005; Hamdorf tions, tumour-promoting inflammation with increased local et al, 2011), sustained phosphorylation inhibits DC matura- and systemic pro-inflammatory cytokines, expression of metal- tion upon stimulation with Toll-like receptor ligands or loproteases potentially promoting invasion and metastasis tumour necrosis factor, as recently demonstrated (Puig-Kro- (Hayashi et al, 1997; da Costa et al, 2005; Allen et al,2010b) ger et al, 2001; Aguilera-Montilla et al, 2013). This role of and overexpression of BCL2L1, which may contribute to resis- ERK activation in myeloid cell differentiation and maturation tance to cell death (Schouten et al, 2002; Amir & Weintraub, during homeostatic conditions might also have valuable 2008; Allen et al, 2010b). However, despite clonality and other implications on the origin and functional alterations of his- malignant hallmarks, LCH cells are characterized by a ‘benign’ tiocytes in LCH. morphology and mitoses are observed at very low and similar Besides the frequent BRAF V600E mutation, single case rates as in normal epidermal LCs. Clonality is essential for reports have described additional mutations/polymorphisms malignancy, but physiological LCs in mice may also have within the BRAF gene locus with potential functional conse- regional clonality, arising from a common precursor (Merad quences, including the somatic mutations BRAF V600D, et al, 2002; Waskow et al, 2008). Karyotypes from LCH biop- BRAF 600DLAT and the germline mutation/poylmorphism sies are typically normal and gross chromosomal lesions have BRAF T599A (Satoh et al, 2012; Kansal et al, 2013). More- not been described (da Costa et al, 2009). Langerhans cell his- over, a complex compound somatic mutation in ARAF with tiocytosis cells do not survive long in cell culture, and no suc- enhanced kinase activity in vitro has also been described in a cessful xenograft model has been reported, further supporting single patient (Nelson et al, 2014). However, extended a malignant character of LCH.

ª 2014 John Wiley & Sons Ltd 5 British Journal of Haematology, 2015, 169, 3–13 Review studies are necessary to elucidate the frequency and signifi- study, though their frequency and functional significance cance of these additional RAF mutations in LCH. remains to be proven in larger series (Fig 1). Using whole exome sequencing on matched LCH lesions In addition to genetic analysis, imaging flow cytometry and peripheral tissue samples obtained from 41 and Western blotting was used to analyse activation of MEK patients, we recently set out to analyse the broader genomic and ERK proteins in CD207+ cells from LCH lesions. landscape of LCH. The overall rate of somatic mutations was MAP2K1 was highly phosphorylated in samples with BRAF remarkably low, at 003 mutations per Mb, or a median of 1 V600E and MAP2K1 mutations. However, MAP2K1 phos- somatic mutation within exons per patient. In this study, we phorylation was minimal in cases with no detectable muta- identified a second recurrent mutated gene locus in LCH, tion in the MAPK pathway. In every case tested, MAPK3/ MAP2K1 (encoding mitogen-activated protein kinase kinase MAPK1 was highly phosphorylated independent of the muta- 1 [MAP2K1, alternatively termed MEK1], also a member of tion or MAP2K1 phosphorylation status (Chakraborty et al, the RAS/RAF/ERK signalling pathway) with a frequency of 2014). Similarly, the original BRAF V600E report by Bada- 33% in lesions with wild-type BRAF (Chakraborty et al, lian-Very et al (2010) also demonstrated ERK activation in 2014). A second study identified mutations through targeted BRAF wild-type lesions by immunohistochemistry. These sequencing of the second and third exons of MAP2K1, in reports support a common critical role of hyperactivation of 50% of wild-type BRAF cases (Brown et al, 2014). Interest- the ERK signalling pathway in LCH pathology independent ingly, both independent studies could only identify mutually of the specific underlying mutation. Deciphering the mecha- exclusive mutation of BRAF and MAP2K1. Functionally, all nisms that drive ERK activation in the cases with undiscov- mutations described within the MAP2K1 gene resulted in the ered MAPK pathway mutations will require extended studies expression of a hyperactive kinase and subsequent constitu- including complimentary methods (e.g. whole genome tive phosphorylation of the downstream targets MAPK3 (also sequencing, RNA sequencing and assessment of epigenetic termed ERK1) and MAPK1 (also termed ERK2) in vitro modifications) to fully assess the causative spectrum of ERK comparable to the effects observed by the expression of activation in LCH. BRAF V600E (Chakraborty et al, 2014). In addition to recur- Activation of ERK may be universal to LCH pathogenesis, rent somatic mutations in BRAF and MAP2K1, we observed but like other diseases driven by MAPK pathway hyperactivity, single cases of mutations of other genes that transcribe it is likely that specific somatic mutations will be associated with MAPK pathway proteins, specifically in ERBB3 and again certain unique clinical features. Although genotype-based risk within the ARAF locus (Chakraborty et al, 2014) in our assessment will require prospective studies in several indepen- dent cohorts, data so far suggest that the genotype does not cor- relate with extent of disease (high versus low-risk) or survival (Badalian-Very et al, 2010; Berres et al, 2014; Bubolz et al, 2014; Chakraborty et al, 2014). However, in our institutional series, the BRAF V600E mutation status correlated significantly with increased risk of initial treatment failure e.g. refractory dis- ease or recurrence (Berres et al, 2014). In addition to the poten- tial relevance of the genotype for clinical risk stratification, it might also have therapeutic implications given that mutations within the MAPK pathway predicted response to specific MAPK pathway inhibitors in vitro. While CD207+ cells with BRAF V600E and MAP2K1 mutation had predictable responses to BRAF and MEK inhibition, responses of BRAF wild-type/ MAP2K1 wild-type lesional cells were highly variable (Chakr- aborty et al, 2014). Therefore, assessment of the mutation status will probably become an important clinical feature of LCH ther- apy to personalize and optimize therapeutic regimens.

Fig 1. Routes to ERK activation in LCH. Model of MAPK pathway LCH as an inflammatory myeloid neoplasia activation resulting from serial phosphorylation from cellular recep- tors through RAS, RAF, MEK and, ultimately, ERK. Estimates of fre- The identification of the frequent BRAF V600E mutation in quency of somatic mutations of BRAF and MAP2K1 are illustrated. 2010 tipped the scales of the historical LCH debate to favour (*) indicates genes with individual case reports of somatic mutations. the classification of LCH as a neoplastic disorder. The muta- ‘Unknown’ indicates ERK activation by mechanisms that have not tion can be detected in various neoplastic diseases and seems yet been defined. While activated ERK has been identified in all lesions studied to date, there remains the possibility (dashed line) to play a pivotal role in their pathology. The impact of BRAF that Langerhans cell histiocytosis (LCH) may arise from alternative V600E appears thereby to depend on the cellular context as mechanisms in some cases. it is frequently observed in more benign conditions, such as

6 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 3–13 Review epidermal nevi and colon polyps, as well as in highly aggres- structural similarities of both cells types, including intracyto- sive malignancies, such as malignant melanoma (Cantwell- plasmatic and especially the common Dorris et al, 2011; Pratilas et al, 2012). expression of the antigen CD1A and the C-type lectin langer- Discovery of BRAF V600E within the lesions provided an in (CD207) (Nezelof et al, 1973). Both features have tradi- important foothold from which to understand pathogenesis tionally been considered to be exclusive to LCs. of LCH, however, the specific impact of BRAF V600E on Langerhans cells represent a specific subpopulation of cells LCH pathogenesis remained elusive. To analyse the poten- of the mononuclear phagocyte system residing in the outer tial function of BRAF V600E mutation as an essential driver layer of the skin, the . They are characterized by of LCH pathology, we recently crossed mice expressing the lower major histocompatibility complex (MHC)-II expres- conditional BRAF V600E allele with transgenic mice sion levels, intermediate CD11c levels as compared to other expressing the cre-recombinase under control of the langer- DCs and high expression of langerin (Merad et al, 2008). in promoter to enforce expression of BRAF V600E in lang- LCs arise from embryonic precursors – mostly fetal liver- erin-expressing DC (differentiated epidermal LCs and derived (Hoeffel et al, 2012) that populate the langerin-expressing lymphoid and non-lymphoid DCs). To skin prior to birth and maintain themselves locally through- determine the significance of the stage during DC differen- out life in steady state conditions (Merad et al, 2002). Fol- tation at which the somatic mutation occurs, we also lowing severe inflammatory injury, such as ultraviolet (UV) crossed mice with the conditional BRAF V600E allele to light exposure, a transient population of LCs can be identi- mice expressing cre-recombinase under the control of fied in the skin that derive from circulating Gr-1hi blood CD11c, which is already expressed in DC progenitors and monocytes (Ginhoux et al, 2006; Sere et al, 2012). However, immature DCs (for further details please see (Berres et al, it remains unclear if these inflammation-associated, mono- 2014). Mice of both strains spontaneously developed classi- cyte-derived LCs residing in the epidermis after UV light cal granuloma-like lesions characterized by the accumulation exposure are equivalent to steady-state LCs in terms of func- of CD207+ histiocytes by 2–6 months of age. The accumu- tion and tissue homeostasis. lation of histiocytes was associated with increased expres- In contrast to a primary embryonic origin of LCs, most sion of specific cytokines and chemokines and the other classical DCs residing in lymphoid as well as the non- recruitment of additional inflammatory cell e.g. macrophag- lymphoid tissue arise from common circulating precursors– es, multi-nucleated giant cells, B cells and T cells (including the pre-DC (Naik et al, 2007; Onai et al, 2007; Liu et al, T regulatory cells), comparable to human LCH lesions. 2009). Pre-DC share a common progenitor with plasmocy- Interestingly, induction of BRAF V600E expression in circu- toid DCs (pDC), which is thus termed common DC precur- lating blood and bone marrow resident DC progenitors sor or CDP. CDPs are localized in the bone marrow and using the CD11c promoter system resulted in a much more originate from a multipotent bone marrow resident myeloid severe and accelerated course, approximating the human precursor named -DC progenitor (MDP), which high-risk LCH phenotype. Taken together, these results pro- gives rise to monocytes and DC but has lost vide evidence that expression of oncogenic BRAF V600E in potential as compared to the granulocyte- progeni- cells within the mononuclear phagocytes system is sufficient tor (GMP) and thereby marks the stage of commitment to to induce LCH-like disease in mice, leading not only to the the mononuclear phagocyte systems during development accumulation of CD207+ histiocytes, but also to the recruit- (reviewed in Merad et al, 2013). ment of additional inflammatory cells and subsequent for- The concept that LCH cells represent transformed cells of mation of granuloma with highly active cytokine LC origin has been recently challenged by the observation expression. These data support the ability of MAPK activa- that the expression of langerin (CD207) and the formation tion in myeloid DC precursors to drive myeloid differentia- of Birbeck granules is not exclusive to LC but can also be tion and granuloma formation in mice, similar to identified in other subpopulations of the mononuclear pathology observed in LCH. We further propose that LCH phagocyte system. These CD207+ DCs constitutively reside in should be defined as an inflammatory myeloid neoplasia all lymphoid and non-lymphoid tissues where LCH lesions characterized by the formation of highly active, inflamma- can be found in patients (Chikwava & Jaffe, 2004; Ginhoux tory granuloma induced by transformed DC clones. et al, 2007; Poulin et al, 2007; Segerer et al, 2008; Helft et al, 2010). This is in striking contrast to the restricted tropism of LCs to the epidermis and skin-draining lymph nodes. Gene LCH as consequence of misguided myeloid expression profiling studies demonstrated that human differentiation CD207+ DCs within LCH lesions only display a minimal profile overlap with differentiated human LCs, while their Revisiting the cell of origin profile is more consistent with those of immature myeloid As discussed above, it has been assumed that aberrant or DC precursors (Allen et al, 2010b). Additionally, the matura- transformed epidermal LCs embody the cellular origin of the tion status of LCH cells within the lesions is heterogenous histiocytes in LCH, which was mainly based on certain with variable CD1A+/CD207 subpopulations (Chikwava &

ª 2014 John Wiley & Sons Ltd 7 British Journal of Haematology, 2015, 169, 3–13 Review

Jaffe, 2004; Coury et al, 2008; Peters et al, 2011) and mortality. Histologically, lesions of high risk patients are extended immunohistological studies were able to identified indistinguishable from those with low risk disease. Addition- expression of the common BRAF V600E mutation not only ally, with the exception of disease recurrence after therapy, in CD207+ cells but also in CD207 cells as well as in all studies fail to correlate the presence of certain mutation CD14+ monocytes (Sahm et al, 2012). with disease outcome or stage. These new findings open up the possibility that So, which mechanisms regulate disease severity and LCH might not, as tradionally speculated, result from the tropism in LCH? Assessing the BRAF V600E mutational accumulation of dysregulated or transformed mature fetal status in circulating cells of patients with LCH, we recently liver-derived epidermal LCs, but may rather arise from observed that in patients with high risk multi-system disease dysregulated differentiation and/or recruitment of precursor and BRAF V600E mutation in lesional DCs, BRAF V600E cells from the bone marrow-derived myeloid lineage. A dys- was also identified in circulating cells and resident bone mar- regulated differentiation of early multipotent myeloid pro- row cells. Contrarily, circulating cells with BRAF V600E genitors as origin of the disease is also consistent with mutation were absent in the blood and bone marrow of all reports of concurrent or serial lesions of more than one patients with single-system low risk disease (Berres et al, histiocytic phenotype in individual cases with overlapping 2014). Lineage analysis further localized the BRAF V600E features of LCH, juvenile xanthogranuloma (JXG) and Erd- mutation to CD11c+ DC as well as CD14+ monocytes in heim-Chester disease (ECD) (Hoeger et al, 2001; Patrizi et al, high-risk patients. These results point to a somatic mutation 2004; Tsai et al, 2010; Haroche et al, 2013; Berres et al, 2014; of a specific common DC and monocyte progenitor in these Chakraborty et al, 2014; Hervier et al, 2014). cases. Indeed, when bone marrow aspirates of patients with circulating BRAF V600E positive cells were analysed, cells carrying the mutation were identified within the CD34+ Misguided myeloid differentiation translate into disease haematopoietic stem cell (HSC) compartment, and clonal severity and dissemination potential for BRAF V600E positive cells was further con- Langerhans cell histiocytosis is characterized by a broad spec- firmed by colony-forming-unit assays in vitro. Interestingly, trum of clinical presentations ranging from single lesions to in single cases where BRAF V600E was identified in CD34+ multiple lesions within a single to multisystem- cells, it was also detectable in the CD19+ B cells as well as ic disease. As discussed above, the involvement of liver, the CD11c+ and CD14+ fractions, but was absent from CD3+ spleen and bone marrow is associated with higher risk of T cells (Berres et al, 2014).

(A) (B) (C)

(D)

Fig 2. Developmental stage of pathological DC precursor defines extent of disease. (A) Somatic mutation of BRAF or other inciting event in CD34+ haematopoietic stem cells or early DC progenitors induces proliferation, maturation and migration of pathological DCs in multiple tissues that results in high-risk multisystem LCH. (B) Somatic mutation of BRAF or other inciting event in a tissue-restricted DC precursor induces pro- liferation, maturation and tissue-limited migration of pathological DCs that results in low-risk multi-system LCH. (C) Somatic mutation of BRAF or other inciting event in mature DC results in proliferation and maturation of pathological DCs leading to low-risk single lesion LCH. (D) Regardless of cell of origin, the pathological DCs recruit ‘bystander’ immune cells in an inflammatory lesion characteristic of LCH. Cells in white areas indicate cells in circulation; cells in grey areas indicate cells that have migrated to tissue targets. LCH, Langerhans Cell Histiocytosis; DC, dendritic cell. 8 ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 3–13 Review

The association of disease severity with detection of BRAF established, the presence of circulating cells that carry the V600E in HSC in the bone marrow is in line with the mur- mutation may become a valuable diagnostic tool to define ine data presented above showing that expression of the high versus low-risk disease. Finally, in patients in whom cir- mutation already at the stage of bone marrow resident DC culating cells bearing the somatic mutation are identified, progenitors resulted in an aggravated and accelerated pheno- persistence of circulating cells with the mutation may be a type with increased mortality as compared to langerin-driven marker with which to follow residual disease (Berres et al, expression, which is limited to the stage of differentiated DC 2014). (Berres et al, 2014). While the Histiocyte Society and other cooperative group We propose that the misguided myeloid differentiation trials have contributed tremendously to the understanding model of LCH pathogenesis would account for the range of and treatment of LCH, overall outcomes remain suboptimal. clinical manifestations in LCH. In this model, the extent of Due to the scientific progress on LCH pathology in the last disease severity and dissemination is not defined by genomic years, we now have the opportunity to move beyond empiri- or functional alteration at the histiocyte level but by the stage cism to rationale strategies. The relative efficacy of the sec- at which pathological ERK activation occurs during myeloid ond generation nucleoside analogue, clofarabine, in patients differentiation (Fig 2). Based on the data discussed above, we refractory to other therapies may be consistent with its hypothesize that if the mutation occurs at the stage of a tis- known activity against immature myeloid cells in AML and sue-restricted precursor or even tissue-resident precursor/DC, myelodysplastic syndrome (Ghanem et al, 2013). disease will be limited to specific organs (multisystem low- In addition to refining the therapeutic profile of chemother- risk) or even a single location (single lesion low risk). On the apy strategies, recurrent somatic mutations in LCH offer an contrary, mutations impacting early myeloid progenitors opportunity to develop targeted therapeutic strategies. Muta- with high proliferative capacity and multipotent potential, tions in the MAPK pathway have been identified in approxi- the disease will be highly aggressive and disseminate to vari- mately 75% of patients with LCH, and drugs that specifically ous organs resulting in high-risk multisystemic disease. In all inhibit kinase activity of RAF, MEK and ERK proteins have cases, the pathological DC seed to the tissue and follow a been developed and are in various stages of therapeutic evalua- common path of terminal differentiation in which they tion for paediatric patients (Belden & Flaherty, 2012). Unlike acquire the expression of CD207 and CD1A and recruit and melanoma or other aggressive malignancies associated with activate additional inflammatory cells, e.g., macrophages, eo- MAPK activation, the overall genomic landscape of LCH sinophils, B cells and T cells, to the lesion, mediated by lesions is relatively quiet, which may make the efficiacy of these altered cytokine/chemokines expression. This will then result agents more durable in LCH than in tumours that can rapidly in the formation of complex LCH granuloma. However, the develop resistance through multiple mechanisms including relative contributions of these recruited ‘innocent bystander’ acquisition of new mutations (Poulikakos & Rosen, 2011; van cells to LCH pathogenesis are uncertain. Allen et al, 2014). An early report of vemurafanib, which has While ERK activiation appears to be universal in LCH, the activity against BRAFV 600E, in patients with mixed ECD and mechanisms through which ERK activation drives pathogene- LCH, demonstrated promising early responses (Haroche et al, sis in myeloid precursors in LCH remain to be defined. 2013). However, the side effect profile of BRAF inhibitors, Interestingly, BRAF V600E has been identified in CD34+ hae- which includes high rates of de novo squamous cell carcinoma matopoeitic cells in patients with hairy cell leukaemia among other toxicities, makes the the risk-benefit profile of (Chung et al, 2014). Similarly, some patients display the these agents in LCH uncertain relative to rapidly fatal BRAF BRAF V600E mutation in hybrid, synchronous or serial V600E-associated malignancies such as melanoma. Dabrafenib, LCH/JXG or LCH/ECD lesions (Berres et al, 2014; Hervier another agent with activity against activated BRAF, is being et al, 2014). Furthermore, mutations in NRAS, upstream evaluated in a paediatric phase I/II study that includes patients from RAF, have been described in ECD, but not LCH (Fig 1) with LCH (clinicaltrials.gov NCT01677741). Efficacy, tolerabil- (Diamond et al, 2013; Emile et al, 2014). The terminal phe- ity and optimal role for targeted therapies along with or notype of cells in which ERK is pathologically activated may instead of chemotherapeutic agents will be defined in future depend on the state of differentiation of the original cell, the clinical trials. somatic mutation, or additional genetic or epigenetic factors that remain to be defined. Conclusions Langerhans cell histiocytosis is a disease caused by somatic Clinical Implications of the misguided myeloid driver mutations at critical stages of myeloid differentiation differentiation model that result in cellular transformation. An important implica- If future studies support the early observation that BRAF tion of the new understanding of LCH biology is the re-defi- V600E confers increased risk of refractory/recurrent disease, nition of LCH as an inflammatory myeloid neoplasia. Like these patients may benefit from prolonged or intensified other neoplastic myeloid disorders, we believe LCH should chemotherapy. Furthermore, once the genetic lesion is be considered under the umbrella of cancer research. Patients

ª 2014 John Wiley & Sons Ltd 9 British Journal of Haematology, 2015, 169, 3–13 Review with LCH will ultimately benefit from inclusion in portfolios Acknowledgement of cooperative cancer networks to be considered for research funding and clinical trial support. The recent advances in the MLB is supported in part by grants of the German Research understanding of LCH pathogenesis also question if ‘Langer- Association (Deutsche Forschungsgemeinschaft, BE 4818/1-1, hans cell histiocytosis’ is the appropriate nomenclature, given SFB TRR57 P07). CEA is supported in part by the National that pathological lesional cells arise from variable points Institutes of Health (NIH), R01 grant CA154489. MM is sup- along the myeloid/monocytic lineage. ‘Histiocytosis X’ may ported by NIH grant CA154947A. CEA and MM are also be more accurate after all. While ERK activation appears to supported by the North American Consortium for Histio- be universal in LCH, pathways of ERK activation and cellular cytosis Research (St. Baldrick’s Foundation). All authors have context in which pathological ERK activation arises are no financial conflicts to disclose. variable. Increased understanding of LCH pathogenesis will provide opportunities to optimize and personalize therapy Author contributions through improved risk-stratification, targeted therapy and assessment of therapy response based on specific molecular All author’s wrote substantial parts of the manuscript and features and origin of the pathological cells. revised all final versions.

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