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Pathogenesis, clinical features, and treatment advances in mastocytosis.
Best Pract Res Clin Haematol 2006; 19(3):595-615BP

Abstract

Systemic mastocytosis (SM) is characterized by the abnormal growth and accumulation of mast cells (MC) in one or more organs. The interaction between the cytokine stem cell factor (SCF) and its cognate receptor, the c-kit receptor tyrosine kinase (KIT), plays a central role in regulating MC growth and differentiation. Whereas germline and somatically acquired activating mutations of KIT have been identified in SM, the issue as to whether individual KIT mutation(s) are necessary and sufficient to cause MC transformation remains unclear based on currently available data. Activating mutations of platelet-derived growth factor receptor-alpha (FIP1 L1-PDGFRA) are identified in a significant number of SM cases that have associated eosinophilia. To date, as with gastrointestinal stromal tumors, activating mutations of KIT and PDGFRA appear to be alternative and mutually exclusive genetic events in SM. The World Health Organization has specified criteria for classification of SM into six major subtypes: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), systemic mastocytosis with an associated clonal hematological non-mast-cell disorder (SM-AHNMD), aggressive systemic mastocytosis (ASM), mast cell leukemia, and mast cell sarcoma. The ability to molecularly classify individual SM cases based on the presence or absence of specific mutations allows for molecularly targeted therapy in a growing number of cases. Imatinib mesylate therapy might result in complete remission of SM cases with wild-type KIT, certain KIT mutations, such as F522C, or the FIP1L1-PDGFRA fusion gene, but not of D816V-KIT-bearing SM. For the latter, interferon-alpha and 2-CdA are potential first- and second-line therapeutic options. Other drugs under investigation include novel tyrosine kinase inhibitors, as well as NF-kappaB inhibitors, which might display greater selectivity towards D816V-KIT as compared to wild type KIT. The pathogenesis of mastocytosis, its major clinical subtypes, and recent treatment advances are discussed in this chapter.

Authors+Show Affiliations

Division of Hematology, Mayo Clinic, Mayo Building W10A, 200 First Street SW, Rochester, MN 55905, USA. pardanani.animesh@mayo.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

16781490

Citation

Pardanani, A, et al. "Pathogenesis, Clinical Features, and Treatment Advances in Mastocytosis." Best Practice & Research. Clinical Haematology, vol. 19, no. 3, 2006, pp. 595-615.
Pardanani A, Akin C, Valent P. Pathogenesis, clinical features, and treatment advances in mastocytosis. Best Pract Res Clin Haematol. 2006;19(3):595-615.
Pardanani, A., Akin, C., & Valent, P. (2006). Pathogenesis, clinical features, and treatment advances in mastocytosis. Best Practice & Research. Clinical Haematology, 19(3), pp. 595-615.
Pardanani A, Akin C, Valent P. Pathogenesis, Clinical Features, and Treatment Advances in Mastocytosis. Best Pract Res Clin Haematol. 2006;19(3):595-615. PubMed PMID: 16781490.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pathogenesis, clinical features, and treatment advances in mastocytosis. AU - Pardanani,A, AU - Akin,C, AU - Valent,P, PY - 2006/6/20/pubmed PY - 2006/9/29/medline PY - 2006/6/20/entrez SP - 595 EP - 615 JF - Best practice & research. Clinical haematology JO - Best Pract Res Clin Haematol VL - 19 IS - 3 N2 - Systemic mastocytosis (SM) is characterized by the abnormal growth and accumulation of mast cells (MC) in one or more organs. The interaction between the cytokine stem cell factor (SCF) and its cognate receptor, the c-kit receptor tyrosine kinase (KIT), plays a central role in regulating MC growth and differentiation. Whereas germline and somatically acquired activating mutations of KIT have been identified in SM, the issue as to whether individual KIT mutation(s) are necessary and sufficient to cause MC transformation remains unclear based on currently available data. Activating mutations of platelet-derived growth factor receptor-alpha (FIP1 L1-PDGFRA) are identified in a significant number of SM cases that have associated eosinophilia. To date, as with gastrointestinal stromal tumors, activating mutations of KIT and PDGFRA appear to be alternative and mutually exclusive genetic events in SM. The World Health Organization has specified criteria for classification of SM into six major subtypes: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), systemic mastocytosis with an associated clonal hematological non-mast-cell disorder (SM-AHNMD), aggressive systemic mastocytosis (ASM), mast cell leukemia, and mast cell sarcoma. The ability to molecularly classify individual SM cases based on the presence or absence of specific mutations allows for molecularly targeted therapy in a growing number of cases. Imatinib mesylate therapy might result in complete remission of SM cases with wild-type KIT, certain KIT mutations, such as F522C, or the FIP1L1-PDGFRA fusion gene, but not of D816V-KIT-bearing SM. For the latter, interferon-alpha and 2-CdA are potential first- and second-line therapeutic options. Other drugs under investigation include novel tyrosine kinase inhibitors, as well as NF-kappaB inhibitors, which might display greater selectivity towards D816V-KIT as compared to wild type KIT. The pathogenesis of mastocytosis, its major clinical subtypes, and recent treatment advances are discussed in this chapter. SN - 1521-6926 UR - https://www.unboundmedicine.com/medline/citation/16781490/Pathogenesis_clinical_features_and_treatment_advances_in_mastocytosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1521-6926(05)00097-6 DB - PRIME DP - Unbound Medicine ER -