Elevated expression of the proto-oncogene c-kit in patients with mastocytosis

Nagata, Hiroshi; Worobec, Alexandra S.; Semere, Tekli; Metcalfe, D D

doi:10.1038/sj.leu.2400906

Cited by 30 publications

(18 citation statements)

References 20 publications

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“…Indeed, increased transcription from KIT in patients with more aggressive forms of mast cell disease associated with MPD has been documented. 72 If this is the case, KIT inhibitors may inhibit ASM, even when driven by an RAS oncogene.…”

Section: Discussionmentioning

confidence: 99%

Repressible transgenic model of NRAS oncogene–driven mast cell disease in the mouse

Wiesner

Jones

Hasz

et al. 2005

Blood

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IntroductionNRAS is mutated in a variety of hematologic disorders, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and various myeloproliferative diseases (MPDs). 1-5 NRAS mutations are also associated with the progression of myelodysplastic and myeloproliferative diseases to overt leukemia. [6][7][8][9] As many as 30% of AMLs harbor mutations resulting in NRAS dysregulation, and the Ras family members (H-, N-, and K-Ras) have long been the subjects of intense investigation regarding their relation to tumorigenesis and cancer. [10][11][12] Ras becomes dysregulated in hematopoietic disease through a number of mechanisms. Constitutively active tyrosine kinases, such as breakpoint-cluster region/Abelson leukemia (BCR-ABL) and mutant FMS-like tyrosine kinase 3 (FLT3), cause increased RAS activation by upstream signal amplification. 13,14 Point mutations in Ras itself (eg, G12V) cause longer association of RAS with guanosine triphosphate (GTP) by reducing GTPase activating protein (GAP) sensitivity of Ras, maintaining an active conformation. [15][16][17][18] Loss of GAPs, such as NF1, result in slower hydrolysis of the GTP gamma phosphate, resulting in prolonged RAS signaling and increased Ras activation. 19 Each of these mechanisms of dysregulation has been implicated in human diseases, including AML.Despite intense scrutiny, the specific contribution Ras dysregulation makes in the development of these diseases has not been determined. Specific interactions between the leukemic target cell and the genetic and epigenetic contexts in which NRAS mutations occur likely explain how the same mutation can result in related, but distinct, myeloid diseases. Finally, whether RAS oncogene products are appropriate therapeutic targets in various myeloid diseases is unclear. A major impediment to elucidating the contribution NRAS mutation makes to the development and maintenance of hematopoietic disease and its suitability as a target is a lack of an appropriate mouse model.Here we report the development of a transgenic mouse model of activated NRAS-driven myeloid disease. Mice develop disease with 100% penetrance in a period of time amenable to pharmacologic intervention and cooperating mutagenesis studies. In addition, the model offers the opportunity to evaluate changes in the hematopoietic system in response to transgene repression and derepression by virtue of the tetracycline transactivator system. Materials and methods Vector construction and generation of FVB/n transgenic miceThe pVav vector was obtained from Dr Jerry Adams at the Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital (Victoria, Australia). The tetracycline transactivator (tTA) was cut from the pRev-TetOff plasmid (Becton Dickinson Clontech, San Jose, CA) and was subcloned into the TOPOII-blunt cloning vector (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions. The tTA fragment was then cut out with EagI and subcloned into pVav cut with EagI. pTRE2-NRASV12-IRES-hCD2 was generated by insert...

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Section: Discussionmentioning

confidence: 99%

Repressible transgenic model of NRAS oncogene–driven mast cell disease in the mouse

Wiesner

Jones

Hasz

et al. 2005

Blood

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“…These are highly clinically variable, with median survival rates of 2 months for MCL (11,12) but virtually no mortality for mild forms. Mastocytosis is characterized by upregulated c-Kit signaling (13) and the vast majority of systemic mastocytoses harbor an imatinib-insensitive activating c-KIT mutation (usually D816V) (14–17), but this cannot explain the wide clinical variability. Understanding normal MC development and its dysregulation in SM is of central importance to developing new therapies for these disorders.…”

Section: Introductionmentioning

confidence: 99%

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

et al. 2015

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Mast cells are critical components of the innate immune system and important for host defense, allergy, autoimmunity, tissue regeneration, and tumor progression. Dysregulated mast cell development leads to systemic mastocytosis, a clinically variable but often devastating family of hematologic disorders. Here we report that induced expression of Lin28, a heterochronic gene and pluripotency factor implicated in driving a fetal hematopoietic program, caused mast cell accumulation in adult mice in target organs such as the skin and peritoneal cavity. In vitro assays revealed a skewing of myeloid commitment in LIN28B-expressing hematopoietic progenitors, with increased levels of LIN28B in common myeloid and basophil-mast cell progenitors altering gene expression patterns to favor cell fate choices that enhanced mast cell specification. In addition, LIN28B-induced mast cells appeared phenotypically and functionally immature, and in vitro assays suggested a slowing of mast cell terminal differentiation in the context of LIN28B upregulation. Finally, interrogation of human mast cell leukemia samples revealed upregulation of LIN28B in abnormal mast cells from patients with systemic mastocytosis (SM). This work identifies Lin28 as a novel regulator of innate immune function and a new protein of interest in mast cell disease.

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“…18,29 KIT is expressed by mast cells and mast cell progenitors, germ cells, and the interstitial cells of Cajal, the pacemaker cells of the gastrointestinal tract. 8,29 Mutations in tyrosine kinase receptor have been documented in different human mast cell disorders such as urticaria pigmentosa or aggressive mastocytosis 12,15 and in a human mast cell leukemia cell line and gastrointestinal stromal tumors (GISTs). 6,9,11 Different abnormalities (point mutations, deletions, and duplications) have been identified in the juxtamembrane domain of c-kit in canine MCTs and MCT cell lines 10,13 and a close correlation was found between the presence of a mutation and tumor aggressiveness.…”

Section: Introductionmentioning

confidence: 99%

Expression of the KIT Protein (CD117) in Primary Cutaneous Mast Cell Tumors of the Dog

Preziosi¹,

Morini²,

Sarli³

2004

J VET Diagn Invest

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Abstract. Thirty-one canine cutaneous masses, diagnosed as mast cell tumors (MCT) by histopathologic analysis, were used to evaluate the immunohistochemical pattern of expression of KIT protein (CD117), a type III tyrosine kinase protein involved in mast cell growth and differentiation. Lesions were graded as I (well differentiated), II (intermediate differentiation), or III (poorly differentiated) according to the following morphologic features: invasiveness, cellularity and cellular morphology, mitotic index, and stromal reaction. Immunohistochemical KIT expression was compared with histologic grade and some histomorphologic features (cell differentiation and nuclear grade) evaluated separately. A possible predictive role of biologic behavior in MCTs for KIT expression was also investigated. Immunohistochemical analysis revealed three different patterns of KIT expression: a cytoplasmic diffuse pattern, a membranous pattern with immunostaining located on the cell surface, and a cytoplasmic perinuclear pattern, where KIT expression was detected in the cytoplasm of the neoplastic mast cells, close to the nucleus. Statistical analysis showed a close relationship between different KIT immunohistochemical patterns and histologic grade (P Ͻ 0.00000), cell differentiation (P Ͻ 0.00000), and nuclear grade (P Ͻ 0.0024). According to Kaplan-Meier-estimated survival curves compared by survival analysis, KIT expression was significantly associated with survival time (P ϭ 0.037) but not cancer-free interval (P ϭ 0.50). Similar to other well-known histomorphological features, KIT expression is a useful parameter of malignancy in cutaneous MCTs. KIT expression also predicted the biological behavior of the tumors in this study.

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Elevated expression of the proto-oncogene c-kit in patients with mastocytosis

Cited by 30 publications

References 20 publications

Repressible transgenic model of NRAS oncogene–driven mast cell disease in the mouse

Repressible transgenic model of NRAS oncogene–driven mast cell disease in the mouse

The role of Lin28b in myeloid and mast cell differentiation and mast cell malignancy

Expression of the KIT Protein (CD117) in Primary Cutaneous Mast Cell Tumors of the Dog

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