Flt-3 and c-kit mutation studies in a spectrum of chronic myeloid disorders including systemic mast cell disease

Pardanani, Animesh; Reeder, Terra L.; Kimlinger, Teresa K.; Baek, Jin Young; Li, Chin Y.; Butterfield, Joseph H.; Tefferi, Ayalew

doi:10.1016/s0145-2126(02)00303-x

Cited by 40 publications

(27 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, it should be noted that so far, most studies analyzing KIT mutations in SM reported on relatively small series of patients with aggressive forms of the disease 2,3,5,7,9,22,29,30 or single case reports. 6,15,41 Despite this, recent review papers 25,42 estimate that the frequency of the D816V KIT mutation in adult patients with SM could be higher than 80%, while the frequency of KIT mutations in the different forms of SM remains quite variable.…”

Section: Discussionmentioning

confidence: 99%

“…6,15,41 Despite this, recent review papers 25,42 estimate that the frequency of the D816V KIT mutation in adult patients with SM could be higher than 80%, while the frequency of KIT mutations in the different forms of SM remains quite variable. 2,3,5,7,9,11,29,30,43 In some studies, such variability could be related to differences in the methods used and/or the type of samples used for the identification of KIT mutations. Accordingly, while Pardanani et al, 30 through the use of DNA sequencing techniques, have only found 14% (1 of 7) D816V ϩ cases in BM samples from patients with ISM, others 5 using more sensitive methods based on the analysis of mRNA by restriction fragment length polymorphism (RFLP) approaches have found the KIT D816V mutation in all of their 11 patients with ISM.…”

Section: Discussionmentioning

confidence: 99%

“…Despite this, the frequency of the D816V KIT mutation in SM is highly variable in the literature, 2,3,7,11 even once the analysis is restricted to patients showing the same type of MCD. 3,5,9,29 Accordingly, in adult patients, the frequency of the D816V KIT mutation varies from 31% 30 to virtually all cases. 5 Such variability could be due to the relatively low number of cases included in most studies, to patient selection with predominance of aggressive versus indolent forms of the disease and/or to the sensitivity of the methods used to assess the presence/absence of KIT mutations, particularly in cases with low MC burden.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Garcia-Montero

Jara‐Acevedo

Teodósio

et al. 2006

Blood

443

480

View full text Add to dashboard Cite

Despite the relevance of the c-kit/stem cell factor (SCF) signaling pathway in mast cell (MC) diseases, the exact frequency of KIT mutations in different compartments of bone marrow (BM) hematopoietic cells of individuals with systemic mastocytosis (SM), and its different diagnostic categories, remains unknown. In this study, we prospectively analyzed the presence of KIT mutations in fluorescence-activated cell-sorting (FACS)-purified populations of BM MCs (n ‫؍‬ 113) and other BM cell compartments (n ‫؍‬ 67) from adults with SM. Our results show the presence of D816V KIT mutation in virtually all adults (93%) with indolent and aggressive forms of SM, except welldifferentiated SM (29%), while other KIT mutations were rarely (< 3%) detected. In around one-third of patients with mutated MCs, the KIT mutation was also detected in CD34 ؉ hematopoietic cells and eosinophils, and, to a lesser extent, in monocytic, neutrophil-lineage BM precursor cells and lymphocytes. Most patient with poor-prognosis SM (81%) carried the KIT mutation in 2 or more BM myeloid cell populations, while this was detected in a smaller proportion (27%) of indolent cases. These results would support the notion that KIT mutation is a hallmark of adult SM where it targets a pluripotent hematopoietic stem cell, and may contribute to explaining previously observed discrepancies in the literature. IntroductionMast cell diseases (MCDs) are a heterogeneous group of disorders characterized by an abnormal proliferation and accumulation of mast cells (MCs) in different tissues. In a relatively high proportion of cases, the clonal nature of the disease can be established on the basis of the demonstration of gain-of-function mutations involving the tyrosine kinase domain of c-kit in lesional skin and bone marrow (BM) cells. [1][2][3][4][5][6][7][8][9] Typically, the A71763T substitution is detected, whereby an aspartate is changed for a valine at codon 816 of the c-kit protein sequence. However, other uncommon somatic (V560G, 10 D815K, 11 D816Y, 2,11,12 D816F, 2,11 D816H, 13 and D820G 14 ) and germ-line (F522C, 15 A533D, 16 K509I, 17 and del419 18 ) mutations, which may result in a ligand-independent activation of the stem cell factor receptor, have been reported, most frequently in individual cases. Presence of the KIT mutations in patients with systemic mastocytosis (SM) is not restricted to BM MCs, but it has also been sporadically reported in other non-MC hematopoietic lineages, 7,[19][20][21][22][23][24] suggesting that expansion of clonal MCs may arise from an uncommitted hematopoietic stem cell. However, attempts to demonstrate the presence of KIT mutation in purified CD34 ϩ hematopoietic precursor cells have failed so far. 25 The pathogenetic relevance of the different KIT mutations in MCDs is still not fully understood; however, their identification has become of major prognostic significance 26 due to the availability of protein kinase inhibitors such as imatinib (STI571, Gleevec; Novartis, Basel, Switzerland). These new targeted drugs hav...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Garcia-Montero

Jara‐Acevedo

Teodósio

et al. 2006

Blood

443

480

View full text Add to dashboard Cite

show abstract

“…Moreover, some tumors had conflicting features of both benignancy and malignancy, and their malignant potential has been labeled uncertain or indeterminate. In recent years, C-kit protein expression and activated gene mutation have been found in GIST [6][7][8][9] , aggressive mastocytosis [10] , mast cell leukemia [11] , ANLL with/without mast cell involvement [10] , myeloproliferative disorders [10] , colon carcinoma [12] and germ cell tumors [13] . Dections of gene mutation have shown a good correlation with biologic behavior in such tumors and providing valuable adjunctive prognostic information.…”

Section: Discussion Discussion Discussion Discussion Discussionmentioning

confidence: 99%

Prognostic value of KIT mutation in gastrointestinal stromal tumors

Liu

Bai²,

Xie³

et al. 2005

WJG

View full text Add to dashboard Cite

Abstract Abstract Abstract AIM:To examine the prevalence and prognostic significance of C-kit gene mutation and analysis the correlation of Ckit gene mutation and the clinicalpathologic parameters of GISTs. METHODS:Eighty-two GISTs were studied for the mutation of C-kit gene by PCR-SSCP, DNA sequence. Statistical comparison were used to analysis the correlation of C-kit gene mutation and clinicalpathology, clinical behavior, recurrence.

show abstract

“…Although D816V is common in SM patients, the reported incidence has been highly inconsistent (5,12,(13)(14)(15)(16), possibly due to patient heterogeneity (8,14 ) or, more importantly, due to the tissues tested and the detection methods used.…”

mentioning

confidence: 99%

Sensitive Detection of KIT D816V in Patients with Mastocytosis

et al. 2006

View full text Add to dashboard Cite

Background: The 2447 A>T pathogenic variation at codon 816 of exon 17 (D816V) in the KIT gene, occurring in systemic mastocytosis (SM), leads to constitutive activation of tyrosine kinase activity and confers resistance to the tyrosine kinase inhibitor imatinib mesylate. Thus detection of this variation in SM patients is important for determining treatment strategy, but because the population of malignant cells carrying this variation is often small relative to the normal cell population, standard molecular detection methods can be unsuccessful. Methods: We developed 2 methods for detection of KIT D816V in SM patients. The first uses enriched sequencing of mutant alleles (ESMA) after BsmAI restriction enzyme digestion, and the second uses an allele-specific competitive blocker PCR (ACB-PCR) assay. We used these methods to assess 26 patients undergoing evaluation for SM, 13 of whom had SM meeting WHO classification criteria (before variation testing), and we compared the results with those obtained by direct sequencing. Results: The sensitivities of the ESMA and the ACB-PCR assays were 1% and 0.1%, respectively. According to the ACB-PCR assay results, 65% (17/26) of patients were positive for D816V. Of the 17 positive cases, only 23.5% (4/17) were detected by direct sequencing. ESMA detected 2 additional exon 17 pathogenic variations, D816Y and D816N, but detected only 12 (70.5%) of the

show abstract

Flt-3 and c-kit mutation studies in a spectrum of chronic myeloid disorders including systemic mast cell disease

Cited by 40 publications

References 17 publications

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

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

Prognostic value of KIT mutation in gastrointestinal stromal tumors

Sensitive Detection of KIT D816V in Patients with Mastocytosis

Contact Info

Product

Resources

About