Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients

Roumier, Christophe; Lejeune-Dumoulin, S.; Renneville, Aline; Goethgeluck, A S; Philippe, N; Fenaux, Pierre; Preudhomme, Claude

doi:10.1038/sj.leu.2404097

Cited by 18 publications

(25 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, only one of the 26 mutation-harboring cases in our series had changes in two genes, namely case 55 which displayed both a FLT3 and a PTPN11 mutation (Table 1). Previous studies of ALL and AML have shown that concomitant changes in the FLT3, NRAS, KRAS, and PTPN11 genes are rare (Loh et al, 2004;Tartaglia et al, 2005;Roumier et al, 2006;Yamamoto et al, 2006), but this is the first report showing that these mutations generally are mutually exclusive also in high hyperdiploid pediatric ALL. Although it cannot be definitely excluded that coexisting mutations are disadvantageous to the cell, the-albeit few-ALL cases reported with mutations in two genes render this explanation less likely.…”

Section: Discussionmentioning

confidence: 78%

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Paulsson

Horvat

Strömbeck

et al. 2007

Genes Chromosomes & Cancer

102

View full text Add to dashboard Cite

Although it has been suggested that mutations of the FLT3, NRAS, KRAS, and PTPN11 genes are particularly frequent in high hyperdiploid (>50 chromosomes) pediatric acute lymphoblastic leukemias (ALLs), this has as yet not been confirmed in a large patient cohort. Furthermore, it is unknown whether mutations of these genes coexist in hyperdiploid cases. We performed mutation analyses of FLT3, NRAS, KRAS, and PTPN11 in a consecutive series of 78 high hyperdiploid ALLs. Twenty-six (33%) of the cases harbored a mutation, comprising six activating point mutations and one internal tandem duplication of FLT3 (7/78 cases; 9.0%), eight codon 12, 13, or 61 NRAS mutations (8/78 cases; 10%), five codon 12 or 13 KRAS mutations (5/78 cases, 6.4%), and seven exon 3 or 13 PTPN11 mutations (7/78 cases; 9.0%). No association was seen between the presence of a mutation in FLT3, NRAS, KRAS, or PTPN11 and gender, age, white blood cell count, or relapse, suggesting that they do not confer a negative prognostic impact. Only one case harbored mutations in two different genes, suggesting that mutations of these four genes are generally mutually exclusive. In total, one third of the cases harbored a FLT3, NRAS, KRAS, or PTPN11 mutation, identifying the RTK-RAS signaling pathway as a potential target for novel therapies of high hyperdiploid pediatric ALLs. V V C 2007 Wiley-Liss, Inc.

show abstract

Section: Discussionmentioning

confidence: 78%

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Paulsson

Horvat

Strömbeck

et al. 2007

Genes Chromosomes & Cancer

102

View full text Add to dashboard Cite

show abstract

“…Contrary to a study showing a high (23%) frequency of mutation in AML-M0, 37 we and others found no mutations in SPI1. 13,38 It seems that mutations of these transcription factors are not an alternative to RUNX1 mutation in AML-M0. However, as we previously reported, ETV6 mutations are infrequent alternatives to RUNX1 mutation in this cohort.…”

Section: Discussionmentioning

confidence: 99%

“…9 Other genes found to be mutated in AML-M0 include FLT3, RAS and PTPN11. [10][11][12][13][14] However, these mutations are considered to be, rather than surrogates, collaborating abnormalities with mutations in transcription factors such as RUNX1. 15 In this study we aimed to identify new molecular alterations that could explain the etiology of AML-M0.…”

Section: Introductionmentioning

confidence: 99%

Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

et al. 2009

View full text Add to dashboard Cite

“…A cooperation between class I mutations and AML1 mutations has also been reported in AML, which supports this hypothesis that mutations affecting AML1 can reproduce those effects. 211,212 The parallel mutational analysis of genes involved in signal transduction pathways (FLT3, RAS, PTPN11) and in myeloid differentiation (AML1, CEBPA) should help clarify this hypothesis. Based on the two-hit model of AML pathogenesis, the frequent association between NPM1 and FLT3-ITD mutations argues for a role of NPM1 in hematopoietic differentiation.…”

Section: Gene Mutations In Acute Myeloid Leukemiamentioning

confidence: 99%

“…209,210 A mechanism of multistep leukemogenesis is in agreement with this hypothesis, particularly in AML, where a combination of events leading to cell proliferation with events leading to block myeloid differentiation (so-called type I mutations and type II mutations, respectively) is strongly suspected. 1,211,212 Due to their prognostic value, the mutational events screening is particularly important in CN-AML patients.…”

Section: Cooperation Between Gene Mutationsmentioning

confidence: 99%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

Self Cite

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

show abstract

Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients

Cited by 18 publications

References 22 publications

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Genome wide molecular analysis of minimally differentiated acute myeloid leukemia

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

Contact Info

Product

Resources

About