1
|
Wang F, Shen H, Li K, Ding Y, Wang J, Sun J. MYH6 suppresses tumor progression by downregulating KIT expression in human prostate cancer. Sci Rep 2024; 14:19685. [PMID: 39181964 PMCID: PMC11344859 DOI: 10.1038/s41598-024-70665-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/20/2024] [Indexed: 08/27/2024] Open
Abstract
Prostate cancer (PRAD) is one of the leading malignancies in men all around the world. Here, we identified Myosin Heavy Chain 6 (MYH6) as a potential tumor suppressor gene in the development of prostate cancer. We found lower expression of MYH6 in prostate cancer tissues, and its lower gene expression was also associated with worse clinical outcomes. In vitro and in vivo assays indicated that overexpressed MYH6 could suppress the proliferation and migration progression of prostate cancer cells. RNA-seq was employed to investigate the mechanism, and KIT Proto-Oncogen (KIT) was determined as the downstream gene of MYH6, which was further confirmed using rescue assays. In all, we provide the evidence that MYH6 could serve as a tumor suppressor in prostate cancer. Our results highlight the potential role of MYH6 in the development of prostate cancer.
Collapse
Affiliation(s)
- Fei Wang
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 26 Daoqian Rd, Suzhou, 215000, Jiangsu, People's Republic of China
| | - Hua Shen
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 26 Daoqian Rd, Suzhou, 215000, Jiangsu, People's Republic of China
| | - Kai Li
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 26 Daoqian Rd, Suzhou, 215000, Jiangsu, People's Republic of China
| | - Yanhong Ding
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 26 Daoqian Rd, Suzhou, 215000, Jiangsu, People's Republic of China
| | - Jianqing Wang
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 26 Daoqian Rd, Suzhou, 215000, Jiangsu, People's Republic of China.
| | - Jian Sun
- Department of Urology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 26 Daoqian Rd, Suzhou, 215000, Jiangsu, People's Republic of China.
| |
Collapse
|
2
|
Brachet-Botineau M, Polomski M, Neubauer HA, Juen L, Hédou D, Viaud-Massuard MC, Prié G, Gouilleux F. Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers. Cancers (Basel) 2020; 12:E240. [PMID: 31963765 PMCID: PMC7016966 DOI: 10.3390/cancers12010240] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/10/2020] [Accepted: 01/13/2020] [Indexed: 12/14/2022] Open
Abstract
Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors.
Collapse
Affiliation(s)
- Marie Brachet-Botineau
- Leukemic Niche and Oxidative metabolism (LNOx), CNRS ERL 7001, University of Tours, 37000 Tours, France;
| | - Marion Polomski
- Innovation Moléculaire et Thérapeutique (IMT), EA 7501, University of Tours, 37000 Tours, France; (M.P.); (L.J.); (D.H.); (M.-C.V.-M.); (G.P.)
| | - Heidi A. Neubauer
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, A-1210 Vienna, Austria;
| | - Ludovic Juen
- Innovation Moléculaire et Thérapeutique (IMT), EA 7501, University of Tours, 37000 Tours, France; (M.P.); (L.J.); (D.H.); (M.-C.V.-M.); (G.P.)
| | - Damien Hédou
- Innovation Moléculaire et Thérapeutique (IMT), EA 7501, University of Tours, 37000 Tours, France; (M.P.); (L.J.); (D.H.); (M.-C.V.-M.); (G.P.)
| | - Marie-Claude Viaud-Massuard
- Innovation Moléculaire et Thérapeutique (IMT), EA 7501, University of Tours, 37000 Tours, France; (M.P.); (L.J.); (D.H.); (M.-C.V.-M.); (G.P.)
| | - Gildas Prié
- Innovation Moléculaire et Thérapeutique (IMT), EA 7501, University of Tours, 37000 Tours, France; (M.P.); (L.J.); (D.H.); (M.-C.V.-M.); (G.P.)
| | - Fabrice Gouilleux
- Leukemic Niche and Oxidative metabolism (LNOx), CNRS ERL 7001, University of Tours, 37000 Tours, France;
| |
Collapse
|
3
|
Barete S. Les mastocytoses. Ann Dermatol Venereol 2014; 141:698-714; quiz 697, 715. [DOI: 10.1016/j.annder.2014.08.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 07/21/2014] [Accepted: 08/29/2014] [Indexed: 01/05/2023]
|
4
|
Jin Y, Ding K, Wang D, Shen M, Pan J. Novel thiazole amine class tyrosine kinase inhibitors induce apoptosis in human mast cells expressing D816V KIT mutation. Cancer Lett 2014; 353:115-23. [DOI: 10.1016/j.canlet.2014.07.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Revised: 07/09/2014] [Accepted: 07/10/2014] [Indexed: 01/05/2023]
|
5
|
A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis. Blood 2014; 123:1059-68. [DOI: 10.1182/blood-2012-12-473777] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Key Points
JAK2R564Q is the first germline JAK2 mutation found to contribute to a familial MPN that involves a residue other than V617. The kinase activity of JAK2R564Q and JAK2V617F are the same, but only V617F is able to escape regulation by SOCS3 and p27.
Collapse
|
6
|
Verstovsek S. Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and progression. Eur J Haematol 2013. [PMID: 23181448 PMCID: PMC3761194 DOI: 10.1111/ejh.12043] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Apart from indolent systemic mastocytosis (SM), which is associated with a favorable prognosis, other subtypes of SM (SM with associated clonal hematologic non–mast cell lineage disease, aggressive SM, and mast cell leukemia – collectively referred to in this review as advanced SM) can be debilitating. The complexity of SM makes both the diagnosis and design of response criteria challenging for clinical studies. The tyrosine kinase KIT has been shown to play a crucial role in the pathogenesis of SM and has been a focal point in the development of targeted therapy. Mutations within various domains of the KIT receptor that lead to constitutive activation have been identified in patients, and those involving the activation loop of the KIT receptor are the mutations most frequently detected in patients with mastocytosis. Aberrant activation of the KIT receptor results in increased production of mast cells in extracutaneous organs that may lead to organ failure or early death. This review discusses the diagnosis and management of patients with advanced SM, including the relevance of KIT in this disease, potential therapies targeting this kinase, and criteria for measuring responses to these therapies.
Collapse
Affiliation(s)
- Srdan Verstovsek
- Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
| |
Collapse
|
7
|
Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40. Blood 2012; 120:4533-43. [PMID: 22936666 DOI: 10.1182/blood-2012-02-407163] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Targeted and immune-based therapies are thought to eradicate cancer cells by different mechanisms, and these approaches could possibly complement each other when used in combination. In this study, we report that the in vivo antitumor effects of the c-KIT inhibitor, dasatinib, on the c-KIT mutant P815 mastocytoma tumor were substantially dependent on T cell-mediated immunity. We found that dasatinib treatment significantly decreased levels of Tregs while specifically enhancing tumor antigen-specific T-cell responses. We sought to further enhance this therapy with the addition of anti-OX40 antibody, which is known to provide a potent costimulatory signal to T cells. The combination of dasatinib and anti-OX40 antibody resulted in substantially better therapeutic efficacy compared with either drug alone, and this was associated with enhanced accumulation of tumor antigen-specific T cells in the tumor microenvironment. Furthermore, the combination regimen inhibited the function of Tregs and also resulted in significantly up-regulated expression of the IFN-γ-induced chemokines CXCL9, 10, and 11 in the tumor microenvironment, which provides a feasible mechanism for the enhanced intratumoral CTL infiltration. These studies delineate a strategy by which targeted therapy and immunotherapy may be combined to achieve superior antitumor responses in cancer patients.
Collapse
|
8
|
Rudich N, Ravid K, Sagi-Eisenberg R. Mast cell adenosine receptors function: a focus on the a3 adenosine receptor and inflammation. Front Immunol 2012; 3:134. [PMID: 22675325 PMCID: PMC3366457 DOI: 10.3389/fimmu.2012.00134] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Accepted: 05/09/2012] [Indexed: 12/13/2022] Open
Abstract
Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation. These observations have marked the receptor that mediates the bronchoconstrictor effect of adenosine on mast cells (MCs), as an attractive drug candidate. Four subtypes (A1, A2a, A2b, and A3) of adenosine receptors have been cloned and shown to display distinct tissue distributions and functions. Animal models have firmly established the ultimate role of the A3 adenosine receptor (A3R) in mediating hyper responsiveness to adenosine in MCs, although the influence of the A2b adenosine receptor was confirmed as well. In contrast, studies of the A3R in humans have been controversial. In this review, we summarize data on the role of different adenosine receptors in mast cell regulation of inflammation and pathology, with a focus on the common and distinct functions of the A3R in rodent and human MCs. The relevance of mouse studies to the human is discussed.
Collapse
Affiliation(s)
- Noam Rudich
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University Tel Aviv, Israel
| | | | | |
Collapse
|
9
|
KIT protein expression and mutational status of KIT gene in pituitary adenomas. Virchows Arch 2012; 460:171-81. [DOI: 10.1007/s00428-011-1185-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2011] [Revised: 12/11/2011] [Accepted: 12/12/2011] [Indexed: 12/15/2022]
|
10
|
Elvevi A, Grifoni F, Branchi F, Gianelli U, Conte D. Severe chronic diarrhea and maculopapular rash: A case report. World J Gastroenterol 2011; 17:3948-52. [PMID: 22025884 PMCID: PMC3198025 DOI: 10.3748/wjg.v17.i34.3948] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 02/26/2011] [Accepted: 03/05/2011] [Indexed: 02/06/2023] Open
Abstract
Systemic mastocytosis (SM) is a heterogeneous disease of the bone marrow characterized by abnormal growth, accumulation and activation of clonal mast cells (MCs). We report a case of SM with multi-organ involvement. A 30-year-old man presented with diarrhea, flushing, maculopapular rash with itching and weight loss. The upper and lower gastrointestinal endoscopies showed macroscopic involvement of stomach and duodenum; mucosal samples from stomach, duodenum, colon and distal ileum showed mucosal infiltration by large, spindle-shaped MCs with abnormal surface molecule expression (CD2 and CD25), a picture fully consistent with SM, according to the World Health Organization diagnostic criteria. A computed tomography scan showed diffuse lymphadenopathy, hepatosplenomegaly and diffuse small bowel involvement. Bone marrow aspirate and biopsy were diagnostic for SM; serum tryptase levels were increased (209 ng/mL, normal values < 20 ng/mL). The conclusive diagnosis was smouldering SM. There were no therapeutic indications except for treatment of symptoms. The patient was strictly followed up because of the risk of aggressive evolution.
Collapse
|
11
|
Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, Reiss I, Ghofrani HA, Weissmann N, Kuebler WM, Seeger W, Grimminger F, Schermuly RT. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respir Res 2011; 12:60. [PMID: 21535881 PMCID: PMC3104382 DOI: 10.1186/1465-9921-12-60] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Accepted: 05/02/2011] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored. METHODS Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies. RESULTS There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling. CONCLUSIONS The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT-rats.
Collapse
|
12
|
Arock M, Valent P. Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives. Expert Rev Hematol 2011; 3:497-516. [PMID: 21083038 DOI: 10.1586/ehm.10.42] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. Organ systems typically involved are the bone marrow, skin, liver and gastrointestinal tract. In most adult patients, the systemic form of mastocytosis (SM) is diagnosed, which includes an indolent subvariant, an aggressive subvariant and a leukemic subvariant, also termed MC leukemia. Whereas in pediatric mastocytosis, which is usually confined to the skin, a number of different KIT mutations and other defects may be detected, the KIT mutation D816V is detectable in most (adult) patients with SM. In a subset of these patients, additional oncogenic factors may lead to enhanced survival and growth of MCs and, thus, to advanced SM. Other factors may lead to MC activation, with consecutive anaphylactic reactions that can be severe or even fatal. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Unfortunately, the prognosis in these patients remains poor, even when treated with novel KIT-targeting agents, polychemotherapy or stem cell transplantation. This article provides a summary of our knowledge on the pathogenesis and on treatment options in SM.
Collapse
Affiliation(s)
- Michel Arock
- Laboratoire de Biologie et Pharmacologie Appliquée, CNRS UMR 8113, Ecole Normale Supérieure de Cachan, 61, Ave du Président Wilson, 94235 Cachan Cedex, France.
| | | |
Collapse
|
13
|
Abnormal gonad development in Kit W-2Bao mice caused by a Kit gene missense mutation. CHINESE SCIENCE BULLETIN-CHINESE 2010. [DOI: 10.1007/s11434-010-4219-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
14
|
Yin CC, Medeiros LJ, Bueso-Ramos CE. Recent advances in the diagnosis and classification of myeloid neoplasms--comments on the 2008 WHO classification. Int J Lab Hematol 2010; 32:461-76. [PMID: 20626469 DOI: 10.1111/j.1751-553x.2010.01246.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The fourth edition of the World Health Organization (WHO) classification of myeloid neoplasms refined the criteria for some previously described myeloid neoplasms and recognized several new entities based on recent elucidation of molecular pathogenesis, identification of new diagnostic and prognostic markers, and progress in clinical management. Protein tyrosine kinase abnormalities, including translocations or mutations involving ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB, and FGFR1, have been used as the basis for classifying myeloproliferative neoplasms (MPN). Two new entities - refractory cytopenia with unilineage dysplasia and refractory cytopenia of childhood have been added to the group of myelodysplastic syndromes (MDS), and 'refractory anemia with excess blasts-1' has been redefined to emphasize the prognostic significance of increased blasts in the peripheral blood. A list of cytogenetic abnormalities has been introduced as presumptive evidence of MDS in cases with refractory cytopenia but without morphologic evidence of dysplasia. The subgroup 'acute myeloid leukemia (AML) with recurrent genetic abnormalities' has been expanded to include more molecular genetic aberrations. The entity 'AML with multilineage dysplasia' specified in the 2001 WHO classification has been renamed 'AML with myelodysplasia-related changes' to include not only cases with significant multilineage dysplasia but also patients with a history of MDS or myelodysplasia-related cytogenetic abnormalities. The term 'therapy-related myeloid neoplasms' is used to cover the spectrum of disorders previously known as t-AML, t-MDS, or t-MDS/MPN occurring as complications of cytotoxic chemotherapy and/or radiation therapy. In this review, we summarize many of these important changes and discuss some of the diagnostic challenges that remain.
Collapse
Affiliation(s)
- C C Yin
- The Department of Hematopathology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
| | | | | |
Collapse
|
15
|
Abstract
Gastrointestinal stromal tumors (GISTs) have emerged from being a poorly understood and therapeutically refractory sarcoma to a tumor whose biology has not only provided insight into a mechanism of oncogenesis but has also led to a rational basis for therapy. Most GISTs are characterized by KIT protein (CD117) expression and constitutive activating mutations in either the c-kit or platelet-derived growth factor receptor α genes. This information can now be obtained from routine formalin-fixed and paraffin-embedded tissue. Because the correct diagnosis is the key to successful treatment of this tumor, it is incumbent on the pathologist to be familiar with the various gross and histologic patterns shown by these tumors. GISTs range from small incidental stromal nodules to large cystic and solid tumor masses. GISTs show a variety of microscopic patterns and therefore several other tumors enter the differential diagnosis. Fortunately, with an understanding of GIST histology, and with the proper use of immunohistochemistry and molecular analysis, a correct diagnosis can usually be made. In addition to the correct diagnosis, several key attributes of the tumor need to be determined because they provide the basis for proper clinical management. This article summarizes the gross, microscopic, and molecular findings of GISTs, and discusses the differential diagnosis and key attributes of this interesting group of neoplasms.
Collapse
|
16
|
Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol 2009; 84:790-4. [PMID: 19890907 DOI: 10.1002/ajh.21561] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cytoreductive therapy in systemic mastocytosis (SM) includes several drugs whose individual merit has not been well characterized. We retrospectively studied 108 Mayo Clinic patients who met the 2008 WHO diagnostic criteria for SM and received at least one cytoreductive drug. The numbers of patients who were evaluable for response to treatment with interferon-alpha with or without prednisone (IFN-alpha), hydroxyurea (HU), imatinib mesylate (IM) or 2-chlorodeoxyadenosine (2-CdA) were 40, 26, 22, and 22, respectively. The corresponding overall (major) response rates, according to recently published consensus criteria, were 53% (18%), 19% (0%), 18% (9%), and 55% (37%). The respective overall response rates in indolent SM, aggressive SM and SM associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD) were 60%, 60%, 45% for IFN-alpha, 0, 0, 21% for HU, 14%, 50%, 9% for IM and 56%, 50%, 55% for 2-CdA. The absence of mast cell mediator release symptoms in IFN-alpha-treated patients and presence of circulating immature myeloid cells in 2-CdA-treated patients predicted inferior response. TET2 mutational status did not influence treatment response. Although the major response rates with these four cytoreductive agents were still suboptimal and HU was mainly used in patients with SM-AHNMD, the current study favors 2-CdA or IFN-alpha as first-line current therapy in SM and identifies patients who are likely to respond to such therapy.
Collapse
Affiliation(s)
- Ken H Lim
- Divisions of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | | | | | | | | |
Collapse
|
17
|
Grimwade LF, Happerfield L, Tristram C, McIntosh G, Rees M, Bench AJ, Boyd EM, Hall M, Quinn A, Piggott N, Scorer P, Scott MA, Erber WN. Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms. Br J Haematol 2009; 147:495-506. [DOI: 10.1111/j.1365-2141.2009.07870.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
18
|
Abstract
Mast cells are still generally viewed as mediators of type I allergic or pseudoallergic reactions. Research over the past 10 years revealed that our view was too small and that mast cells are of key importance in innate immunity and also types II, III and IV adaptive immune reactions. Understanding their role in modulating and amplifying of inflammatory responses provides important insights into the pathogenesis of skin diseases such as psoriasis, atopic dermatitis, bullous pemphigoid or the control of infections. This helps us to understand the course of these diseases, their trigger mechanisms, and, the new role of agents, which can modulate the function of mast cells. These insights will help to develop new therapeutic approaches.
Collapse
Affiliation(s)
- Manfred Kneilling
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany
| | | |
Collapse
|
19
|
Current World Literature. Curr Opin Allergy Clin Immunol 2009; 9:386-90. [DOI: 10.1097/aci.0b013e32832eb836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
20
|
Abstract
The presence of melanin pigment within the iris is responsible for the visual impression of human eye colouration with complex patterns also evident in this tissue, including Fuchs' crypts, nevi, Wolfflin nodules and contraction furrows. The genetic basis underlying the determination and inheritance of these traits has been the subject of debate and research from the very beginning of quantitative trait studies in humans. Although segregation of blue-brown eye colour has been described using a simple Mendelian dominant-recessive gene model this is too simplistic, and a new molecular genetic perspective is needed to fully understand the biological complexities of this process as a polygenic trait. Nevertheless, it has been estimated that 74% of the variance in human eye colour can be explained by one interval on chromosome 15 that contains the OCA2 gene. Fine mapping of this region has identified a single base change rs12913832 T/C within intron 86 of the upstream HERC2 locus that explains almost all of this association with blue-brown eye colour. A model is presented whereby this SNP, serving as a target site for the SWI/SNF family member HLTF, acts as part of a highly evolutionary conserved regulatory element required for OCA2 gene activation through chromatin remodelling. Major candidate genes possibly effecting iris patterns are also discussed, including MITF and PAX6.
Collapse
Affiliation(s)
- Richard A Sturm
- Melanogenix Group, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia.
| | | |
Collapse
|
21
|
A novel KIT missense mutation in one Chinese family with piebaldism. Arch Dermatol Res 2009; 301:387-9. [PMID: 19430803 DOI: 10.1007/s00403-009-0955-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2009] [Revised: 04/05/2009] [Accepted: 04/19/2009] [Indexed: 10/20/2022]
Abstract
Piebaldism is an autosomal dominant disorder characterized by congenital leukoderma, mostly affecting forehead, abdomen and knee. Previous studies have revealed that piebaldism is caused by mutations of the KIT gene, which encodes the cell surface transmembrane tyrosine kinase receptor for KIT ligand. We reported here a Chinese Han family with piebaldism, and performed mutation detection of KIT gene by direct sequencing. A novel missense mutation C58G was identified in the patients, but not in the healthy individuals from the family and 100 unrelated controls. This study contributes to the database on KIT in piebaldism and enriches the knowledge about the genotype/phenotype correlation.
Collapse
|