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   Bone marrow niche dysregulation in myeloproliferative neoplasms
Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1189-1200
Natalia Curto-Garcia, Claire Harrison and Donal P McLornan
Department of Hematology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
 ABSTRACT
The bone marrow niche is a complex and dynamic structure com- posed of a multitude of cell types which functionally create an interactive network facilitating hematopoietic stem cell develop- ment and maintenance. Its specific role in the pathogenesis, response to therapy, and transformation of myeloproliferative neoplasms has only recently been explored. Niche functionality is likely affected not only by the genomic background of the myeloproliferative neoplasm-associated mutated hematopoietic stem cells, but also by disease-associated ‘chronic inflammation’, and subsequent adaptive and innate immune responses. ‘Cross-talk’ between mutated hematopoietic stem cells and multiple niche components may contribute to propagating disease progression and mediating drug resistance. In this timely article, we will review current knowledge surrounding the deregulated bone marrow niche in myelopro- liferative neoplasms and suggest how this may be targeted, either directly or indirectly, potentially influencing therapeutic choices both now and in the future.
Introduction
‘Philadelphia chromosome negative’ myeloproliferative neoplasms (MPN) are a group of relatively rare hematologic diseases characterized by a clonal proliferation of blood cells, most commonly secondary to acquired hematopoietic stem cell (HSC) mutations that directly or indirectly induce upregulation of the JAK-STAT pathway. The 2016 World Health Organization consensus recognizes the following categories under the MPN classification: chronic myeloid leukemia BCR-ABL+, chronic neutrophilic leukemia, essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF) (which includes both the prefibrotic/early stage and overt fibrotic stage), chronic eosinophilic leukemia not otherwise specified, and MPN-unclassifiable.1 Recent analyses estimate the incidence rates of the classi- cal ‘Philadelphia negative’-MPN PV, ET and PMF as 0.7-2.6 cases, 0.34-1.7 cases and 0.1-1.0 cases per 100,000 patients-per-year, respectively.2 Median age at diagnosis is variable, estimated at between 69-76 years for PMF, 65-74 years for PV, and 64- 73 years for ET, although MPN has been described in many younger patients and can manifest at any age.3 Regarding clinical features, these disorders produce a markedly heterogeneous clinical phenotype. For example, in PMF, patients may range from those lacking any discernible symptomatology to those describing debilitating constitutional symptoms, abdominal discomfort due to splenomegaly, bone pain, and symptomatic anemia, amongst others. The most common compli- cations linked to MPN are thrombotic and hemorrhagic events and an inherent risk of leukemic transformation that is dependent upon the underlying MPN pheno- type; this risk is higher for PMF (estimated at a range of 10-20% in the first 10 years from diagnosis) and much lower for both PV (2.3%) and ET (1%).4 These figures reflect historical data, and it is likely that with the move away from consecutive cytotoxic therapeutic approaches, blastic transformation rates may well be lower.
Following the pivotal reports in 2005 by four different research groups concern- ing the prevalence of the acquired somatic mutation JAK2 V617F in MPN, knowl- edge of the mutational landscape continues to expand.5-8 The JAK2 V617F mutation is present in approximately 98% of PV patients, and has an estimated incidence in ET and MF of 50% and 60%, respectively. Mutations in the thrombopoietin recep- tor (MPL) are described in approximately 3% of ET and 5-8% of MF cases, whereas mutations in calreticulin (CALR) are evident in 25% of ET and 30% of MF
    Correspondence:
CLAIRE HARRISON
claire.harrison@gstt.nhs.uk
Received: November 18, 2019. Accepted: February 6, 2020. Pre-published: April 2, 2020.
doi:10.3324/haematol.2019.243121
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1189
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