Impaired function of bone marrow stromal cells in systemic mastocytosis

Nemeth, Michael J.; Wilson, Todd M.; Ren, Jiaqiang; Sabatino, Marianna; Stroncek, David; Krepuska, Miklós; Bai, Yun; Robey, Pamela Gehron; Metcalfe, Dean D.; Mezey, Éva

doi:10.1016/j.scr.2015.04.005

Cited by 9 publications

(7 citation statements)

References 28 publications

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“…39 These results are in line with recent observations by Nemeth et al who described the presence of abnormal MSCs with slow proliferation, signs of senescence, and impaired osteogenic function (vs normal MSC colonies) in SM patients. 60 Of note, these authors did not find the KIT D816V mutation in cultured BM MSCs from any of the 5 SM patients they analyzed. The apparent discrepancy between these findings and our observations could be due to the relatively low number of patients analyzed or to a preferential growth of normal vs mutated MSCs after medium to long-term in vitro culture.…”

Section: Discussionmentioning

confidence: 88%

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Garcia-Montero¹,

Jara‐Acevedo

Álvarez‐Twose

et al. 2016

Blood

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Key Points• Acquisition of the KIT D816V mutation in an early pluripotent progenitor cell confers ISM cases a greater risk for disease progression.• Despite the early acquisition of the KIT mutation, onset of clinical symptoms of ISM is often delayed to middle adulthood.Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSCmutated patients had multilineage KIT mutation (100% vs 30%, P 5 .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P 5 .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P 5 .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P 5 .04), and a shorter progression-free survival (P £ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome. (Blood. 2016;127(6):761-768)

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Section: Discussionmentioning

confidence: 88%

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Garcia-Montero¹,

Jara‐Acevedo

Álvarez‐Twose

et al. 2016

Blood

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“…In accordance with other studies, we found c-KIT expression in granulated cells, both in the dermis and in the adventitia of collectors. The cells most likely representing mast cells [ 59 ]. CD34 clearly demarcates fibrocytes in the adventitia, which is in line with previous studies [ 28 ], and the use of CD34 as a marker for the diagnostics of fibrous tumors [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Morphological and Molecular Characterization of Human Dermal Lymphatic Collectors

Hasselhof¹,

Sperling²,

Buttler³

et al. 2016

PLoS ONE

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Millions of patients suffer from lymphedema worldwide. Supporting the contractility of lymphatic collectors is an attractive target for pharmacological therapy of lymphedema. However, lymphatics have mostly been studied in animals, while the cellular and molecular characteristics of human lymphatic collectors are largely unknown. We studied epifascial lymphatic collectors of the thigh, which were isolated for autologous transplantations. Our immunohistological studies identify additional markers for LECs (vimentin, CCBE1). We show and confirm differences between initial and collecting lymphatics concerning the markers ESAM1, D2-40 and LYVE-1. Our transmission electron microscopic studies reveal two types of smooth muscle cells (SMCs) in the media of the collectors with dark and light cytoplasm. We observed vasa vasorum in the media of the largest collectors, as well as interstitial Cajal-like cells, which are highly ramified cells with long processes, caveolae, and lacking a basal lamina. They are in close contact with SMCs, which possess multiple caveolae at the contact sites. Immunohistologically we identified such cells with antibodies against vimentin and PDGFRα, but not CD34 and cKIT. With Next Generation Sequencing we searched for highly expressed genes in the media of lymphatic collectors, and found therapeutic targets, suitable for acceleration of lymphatic contractility, such as neuropeptide Y receptors 1, and 5; tachykinin receptors 1, and 2; purinergic receptors P2RX1, and 6, P2RY12, 13, and 14; 5-hydroxytryptamine receptors HTR2B, and 3C; and adrenoceptors α2A,B,C. Our studies represent the first comprehensive characterization of human epifascial lymphatic collectors, as a prerequisite for diagnosis and therapy.

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“…The use of the ABC DLBCL gene-expression signature has been proposed as a biomarker to enrich for patients with chronic active BCR signaling that are more likely to be sensitive to ibrutinib treatment, based on the higher response rate in ABC than GCB DLBCL (37% vs 5%, respectively). 4 In the study by Szydlowski et al, expression of FOXO1, which was absent in 20% of the tumors, was proposed as a potential biomarker to identify patients who should be resistant to SYK or PI3K/AKT inhibitors. Although these biomarkers are undoubtedly valuable, the majority of patients that they would select would still be expected to be unresponsive to treatment.…”

Section: 9mentioning

confidence: 99%

“…Gas6 2/2 mice are protected against lethal venous thrombosis, explained by a weakened platelet aggregation response 3 and by decreased tissue factor expression in the endothelium. 4 In the presence of endothelium-derived Gas6, tumor cells induce phosphorylation of Erk1/2 in endothelial cells, leading to an upregulation of Ptges production. Ptges produces PGE 2 from prostaglandin H 2 (PGH 2 ), which, on secretion, interacts with the EP3 receptor on platelets to trigger platelet activation and promote thrombosis.…”

Section: Kaisa E Happonen and Björn Dahlbäck Lund Universitymentioning

confidence: 99%

“…6 A similar response rate was observed in the phase 1/2 clinical trial with ibrutinib in patients with relapsed/refractory DLBCL, with 25% (20/80) of patients responding to treatment. 4 Interestingly, however, no patient with DLBCL responded to treatment with the selective PI3Kd inhibitor idelalisib in the phase 1 study of relapsed/refractory non-Hodgkin lymphoma. 7 The lack of responses in that study is probably a result of the small number of enrolled DLBCL patients (n 5 9), but may also indicate that targeting PI3Kd is insufficient to completely block the tonic BCR signal.…”

mentioning

confidence: 99%

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