Molecular defects in mastocytosis: KIT and beyond KIT

Siham Bibi; Florent Langenfeld; Sylvie Jeanningros; Fabienne Brenet; Erinn Soucie; Olivier Hermine; Gandhi Damaj; Patrice Dubreuil; Michel Arock

doi:10.1016/j.iac.2014.01.009

Molecular defects in mastocytosis: KIT and beyond KIT

Immunol Allergy Clin North Am. 2014 May;34(2):239-62. doi: 10.1016/j.iac.2014.01.009.

Authors

Siham Bibi¹, Florent Langenfeld¹, Sylvie Jeanningros¹, Fabienne Brenet², Erinn Soucie², Olivier Hermine³, Gandhi Damaj⁴, Patrice Dubreuil⁵, Michel Arock⁶

Affiliations

¹ Molecular Oncology and Pharmacology, LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, 61, Avenue du Président Wilson, Cachan 94235, France.
² Signaling, Hematopoiesis and Mechanism of Oncogenesis, Inserm U1068, CRCM, 27, Bd Leï Roure BP 30059, Marseille 13009, France; Institut Paoli-Calmettes, 232, Bd Sainte-Marguerite BP 156, Marseille 13009, France; Aix-Marseille University, UM 105, 27, Bd Leï Roure BP 30059, Marseille 13284, France; CNRS, UMR7258, CRCM, 27, Bd Leï Roure BP 30059, Marseille 13009, France.
³ Clinical Hematology Department, Faculty of Medicine and AP-HP Necker-Enfants Malades, Paris Descartes University, 12, Rue de l'École de Médecine, 75006, Paris, France; Faculty of Medicine et AP-HP Necker-Enfants Malades, Mastocytosis Reference Center, 149, Rue de Sèvres, 75015 Paris, Paris Cedex 15 75743, France.
⁴ Faculty of Medicine et AP-HP Necker-Enfants Malades, Mastocytosis Reference Center, 149, Rue de Sèvres, 75015 Paris, Paris Cedex 15 75743, France; Clinical Hematology Department, Hôpital Sud, CHU Amiens, Ave René Laënnec - Salouël, Amiens 80054, France.
⁵ Signaling, Hematopoiesis and Mechanism of Oncogenesis, Inserm U1068, CRCM, 27, Bd Leï Roure BP 30059, Marseille 13009, France; Institut Paoli-Calmettes, 232, Bd Sainte-Marguerite BP 156, Marseille 13009, France; Aix-Marseille University, UM 105, 27, Bd Leï Roure BP 30059, Marseille 13284, France; CNRS, UMR7258, CRCM, 27, Bd Leï Roure BP 30059, Marseille 13009, France; Faculty of Medicine et AP-HP Necker-Enfants Malades, Mastocytosis Reference Center, 149, Rue de Sèvres, 75015 Paris, Paris Cedex 15 75743, France.
⁶ Molecular Oncology and Pharmacology, LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, 61, Avenue du Président Wilson, Cachan 94235, France. Electronic address: [email protected].

PMID: 24745672
DOI: 10.1016/j.iac.2014.01.009

Abstract

In all variants of mastocytosis, activating KIT mutations are frequently found. In adults, neoplastic mast cells (MCs) cells show the KIT mutation D816V, whereas in children, MCs invading the skin are frequently positive for non-KIT D816V mutations. The clinical course and prognosis of the disease vary among patients with systemic mastocytosis (SM). Additional KIT-independent molecular defects might cause progression. Additional oncogenic lesions have recently been identified in advanced SM. In advanced SM the presence of additional genetic lesions or altered signaling worsening the prognosis might lead to the use of alternative therapies such as combined antisignaling targeted treatments or stem cell transplantation.

Keywords: ASXL1; KIT; Mutation; Signaling; Spliceosome; Systemic mastocytosis; TET2; Targeted therapy.

MeSH terms

Bone Marrow / drug effects
Bone Marrow / metabolism
Bone Marrow / pathology
Cell Proliferation
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Dioxygenases
Exons
Gene Expression Regulation, Neoplastic*
Hematologic Neoplasms / diagnosis
Hematologic Neoplasms / drug therapy
Hematologic Neoplasms / genetics*
Hematologic Neoplasms / pathology
Humans
Mast Cells / drug effects
Mast Cells / metabolism*
Mast Cells / pathology
Mastocytosis / diagnosis
Mastocytosis / drug therapy
Mastocytosis / genetics*
Mastocytosis / pathology
Mutation
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-kit / genetics*
Proto-Oncogene Proteins c-kit / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Signal Transduction
Spliceosomes / genetics*
Spliceosomes / metabolism
Spliceosomes / pathology
Stem Cell Factor / genetics
Stem Cell Factor / metabolism

Substances

ASXL1 protein, human
DNA-Binding Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Repressor Proteins
Stem Cell Factor
Dioxygenases
TET2 protein, human
Proto-Oncogene Proteins c-kit