Rarity of dominant-negative mutations of the G-CSF receptor in patients with blast crisis of chronic myeloid leukemia or de novo acute leukemia

Carapeti, Melina; Soede-Bobok, Amrita A.; Hochhaus, Andreas; Sill, Heinz; Touw, Ivo P.; Goldman, John M.; Cross, Nicholas C. P.

doi:10.1038/sj.leu.2400697

Cited by 24 publications

(18 citation statements)

References 8 publications

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“…In contrast, our method of direct amplification of tumor DNA to generate amplicons for resequencing has been shown to reliably detect mutations that are present in at least 33% of cells (this applies to all genes sequenced in this study). 26 Consistent with previous reports, 23,52,53 no CSF3R mutations were detected in the de novo AML samples, suggesting that CSF3R mutations are rare in de novo AML.…”

Section: Discussionsupporting

confidence: 80%

Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia

Link¹,

Kunter²,

Kasai

et al. 2007

Blood

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Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis. (Blood. 2007;110: [1648][1649][1650][1651][1652][1653][1654][1655]

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Section: Discussionsupporting

confidence: 80%

Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia

Link¹,

Kunter²,

Kasai

et al. 2007

Blood

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“…Whereas truncation mutations of CSF3R are present in 78% of cases of MDS/AML in patients with SCN (10), they are observed in only 1%-2% of de novo AML cases (10,30,31). These mutations are acquired and achieve clonal dominance in the human bone marrow microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5

Liu¹,

Kunter²,

Krem³

et al. 2008

J. Clin. Invest.

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A fundamental property of leukemic stem cells is clonal dominance of the bone marrow microenvironment. Truncation mutations of CSF3R, which encodes the G-CSF receptor (G-CSFR), are implicated in leukemic progression in patients with severe congenital neutropenia. Here we show that expression of a truncated mutant Csf3r in mice confers a strong clonal advantage at the HSC level that is dependent upon exogenous G-CSF. G-CSF-induced proliferation, phosphorylation of Stat5, and transcription of Stat5 target genes were increased in HSCs isolated from mice expressing the mutant Csf3r. Conversely, the proliferative advantage conferred by the mutant Csf3r was abrogated in myeloid progenitors lacking both Stat5A and Stat5B, and HSC function was reduced in mice expressing a truncated mutant Csf3r engineered to have impaired Stat5 activation. These data indicate that in mice, inappropriate Stat5 activation plays a key role in establishing clonal dominance by stem cells expressing mutant Csf3r.

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“…Due to the low frequency of the G-CSF-R_785Lys allele, we did not identify any patient or control individual with a homozygous G-CSF-R_785Lys/Lys genotype in our cohorts. Interestingly, although in the currently available literature only few patients with MDS were screened for mutations in the intracellular domain of the G-CSF-R, 32,33 Carapeti et al 34 reported a patient with secondary AML following high-risk MDS who displayed the homozygous G-CSF-R_785Lys/Lys genotype. Because DNA from nonhematopoietic cells from this patient was …”

Section: Discussionmentioning

confidence: 99%

A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome

Wölfler

Erkeland

Bodner

et al. 2005

Blood

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Rarity of dominant-negative mutations of the G-CSF receptor in patients with blast crisis of chronic myeloid leukemia or de novo acute leukemia

Cited by 24 publications

References 8 publications

Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia

Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia

Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5

A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome

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