Clonal Analysis of NRAS Activating Mutations in KIT-D816V Systemic Mastocytosis

Overview

Journal Haematologica

Specialty Hematology

Date 2010 Dec 8

PMID 21134978

Citations 44

Authors

Todd M Wilson

Irina Maric

Olga Simakova

Yun Bai

Eunice Ching Chan

Nicolas Olivares

Melody Carter

Dragan Maric

Jamie Robyn

Dean D Metcalfe

Affiliations

Soon will be listed here.

Abstract

Cooperating genetic events are likely to contribute to the phenotypic diversity of KIT-D816V systemic mastocytosis. In this study, 44 patients with KIT-D816V systemic mastocytosis were evaluated for coexisting NRAS, KRAS, HRAS or MRAS mutations. Activating NRAS mutations were identified in 2 of 8 patients with advanced disease. NRAS mutations were not found in patients with indolent systemic mastocytosis. To better understand the clonal evolution of mastocytosis, we evaluated the cell compartments impacted by the NRAS and KIT mutations. Clonal mast cells harbored both mutations. KIT-D816V was not detected in bone marrow CD34(+) progenitors, whereas the NRAS mutation was present. These findings suggest that NRAS mutations may have the potential to precede KIT-D816V in clonal development. Unlike other mature lineages, mast cell survival is dependent on KIT and the presence of these two activating mutations may have a greater impact on the expansion of this cell compartment and in resultant disease severity.

Citing Articles

Genetic Changes in Mastocytes and Their Significance in Mast Cell Tumor Prognosis and Treatment.

Zmorzynski S, Kimicka-Szajwaj A, Szajwaj A, Czerwik-Marcinkowska J, Wojcierowski J Genes (Basel). 2024; 15(1).

PMID: 38275618 PMC: 10815783. DOI: 10.3390/genes15010137.

Antibody-Based and Cell Therapies for Advanced Mastocytosis: Established and Novel Concepts.

Valent P, Akin C, Arock M, Gleixner K, Greinix H, Hermine O Int J Mol Sci. 2023; 24(20).

PMID: 37894806 PMC: 10607143. DOI: 10.3390/ijms242015125.

MITF Downregulation Induces Death in Human Mast Cell Leukemia Cells and Impairs IgE-Dependent Degranulation.

Proano-Perez E, Olle L, Guo Y, Aparicio C, Guerrero M, Munoz-Cano R Int J Mol Sci. 2023; 24(4).

PMID: 36834926 PMC: 9961600. DOI: 10.3390/ijms24043515.

CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in D816V Neoplastic Mast Cells.

Schneeweiss-Gleixner M, Filik Y, Stefanzl G, Berger D, Sadovnik I, Bauer K Cancers (Basel). 2022; 14(13).

PMID: 35804842 PMC: 9264943. DOI: 10.3390/cancers14133070.

Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis.

Reiter A, Schwaab J, DeAngelo D, Gotlib J, Deininger M, Pettit K Blood Adv. 2022; 6(21):5750-5762.

PMID: 35640224 PMC: 9647833. DOI: 10.1182/bloodadvances.2022007539.

References

Christiansen D, Andersen M, Desta F, Pedersen-Bjergaard J . Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2005; 19(12):2232-40. DOI: 10.1038/sj.leu.2404009. View

Shefler I, Mekori Y, Mor A . Stimulation of human mast cells by activated T cells leads to N-Ras activation through Ras guanine nucleotide releasing protein 1. J Allergy Clin Immunol. 2008; 122(6):1222-5. DOI: 10.1016/j.jaci.2008.07.024. View

Ustun C, Corless C, Savage N, Fiskus W, Manaloor E, Heinrich M . Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. Leuk Res. 2008; 33(5):735-41. DOI: 10.1016/j.leukres.2008.09.027. View

Wiesner S, Jones J, Hasz D, Largaespada D . Repressible transgenic model of NRAS oncogene-driven mast cell disease in the mouse. Blood. 2005; 106(3):1054-62. DOI: 10.1182/blood-2004-08-3306. View

Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P . Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008; 22(5):915-31. DOI: 10.1038/leu.2008.19. View

Aichberger K, Sperr W, Gleixner K, Kretschmer A, Valent P . Treatment responses to cladribine and dasatinib in rapidly progressing aggressive mastocytosis. Eur J Clin Invest. 2008; 38(11):869-73. DOI: 10.1111/j.1365-2362.2008.02036.x. View

Yeang C, McCormick F, Levine A . Combinatorial patterns of somatic gene mutations in cancer. FASEB J. 2008; 22(8):2605-22. DOI: 10.1096/fj.08-108985. View

Sotlar K, Bache A, Stellmacher F, Bultmann B, Valent P, Horny H . Systemic mastocytosis associated with chronic idiopathic myelofibrosis: a distinct subtype of systemic mastocytosis associated with a [corrected] clonal hematological non-mast [corrected] cell lineage disorder carrying the activating point mutations.... J Mol Diagn. 2008; 10(1):58-66. PMC: 2175544. DOI: 10.2353/jmoldx.2008.070061. View

Ishikawa Y, Kiyoi H, Tsujimura A, Miyawaki S, Miyazaki Y, Kuriyama K . Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia. Eur J Haematol. 2009; 83(2):90-8. DOI: 10.1111/j.1600-0609.2009.01261.x. View

10.

Akin C, Kirshenbaum A, Semere T, Worobec A, Scott L, Metcalfe D . Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells, and myelomonocytic cells in patients with mastocytosis. Exp Hematol. 2000; 28(2):140-7. DOI: 10.1016/s0301-472x(99)00145-9. View

11.

Tefferi A, Levine R, Lim K, Abdel-Wahab O, Lasho T, Patel J . Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009; 23(5):900-4. PMC: 4654631. DOI: 10.1038/leu.2009.37. View

12.

Parikh C, Subrahmanyam R, Ren R . Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice. Blood. 2006; 108(7):2349-57. PMC: 1895567. DOI: 10.1182/blood-2004-08-009498. View

13.

Shih L, Liang D, Huang C, Chang Y, Lai C, Lin T . Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia. 2007; 22(2):303-7. DOI: 10.1038/sj.leu.2404995. View

14.

Maric I, Robyn J, Metcalfe D, Fay M, Carter M, Wilson T . KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities. J Allergy Clin Immunol. 2007; 120(3):680-7. DOI: 10.1016/j.jaci.2007.05.024. View

15.

Nagata H, Worobec A, Oh C, Chowdhury B, Tannenbaum S, Suzuki Y . Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995; 92(23):10560-4. PMC: 40651. DOI: 10.1073/pnas.92.23.10560. View

16.

Kulka M, Fukuishi N, Metcalfe D . Human mast cells synthesize and release angiogenin, a member of the ribonuclease A (RNase A) superfamily. J Leukoc Biol. 2009; 86(5):1217-26. PMC: 2774883. DOI: 10.1189/jlb.0908517. View

17.

Shih L, Huang C, Wang P, Wu J, Lin T, Dunn P . Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia. 2004; 18(3):466-75. DOI: 10.1038/sj.leu.2403274. View

18.

Illmer T, Thiede C, Fredersdorf A, Stadler S, Neubauer A, Ehninger G . Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts. Clin Cancer Res. 2005; 11(9):3217-24. DOI: 10.1158/1078-0432.CCR-04-2232. View

19.

Garcia-Montero A, Jara-Acevedo M, Teodosio C, Sanchez M, Nunez R, Prados A . KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006; 108(7):2366-72. DOI: 10.1182/blood-2006-04-015545. View

20.

Speck N, Gilliland D . Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002; 2(7):502-13. DOI: 10.1038/nrc840. View