An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia

Germeshausen, Manuela; Schulze, Harald; Kratz, Christian P.; Wilkens, Ludwig; Repp, Roland; Shannon, Kevin; Welte, Karl; Ballmaier, Matthias

doi:10.1038/sj.leu.2403663

Cited by 31 publications

(14 citation statements)

References 36 publications

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“…In addition, SCN patients developed AML prior to the advent of G-CSF therapy. In line with this, one SCN patient progressed to CMML in the absence of G-CSF treatment, but expressed a truncated G-CSFR (85). Thus it is possible that the mutant receptor form may have a selective advantage in the absence of treatment, perhaps due to the elevated G-CSF levels seen in SCN patients as a result of their neutropenia (63).…”

Section: Resultssupporting

confidence: 58%

Granulocyte Colony-Stimulating Factor Receptor Mutations in Myeloid Malignancy

Liongue

Ward

2014

Front. Oncol.

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Granulocyte colony-stimulating factor is a cytokine able to stimulate both myelopoiesis and hematopoietic stem cell mobilization, which has seen it used extensively in the clinic to aid hematopoietic recovery. It acts specifically via the homodimeric granulocyte colony-stimulating factor receptor (G-CSFR), which is principally expressed on the surface of myeloid and hematopoietic progenitor cells. A number of pathogenic mutations have now been identified in CSF3R, the gene encoding G-CSFR. These fall into distinct classes, each of which is associated with a particular spectrum of myeloid disorders, including malignancy. This review details the various CSF3R mutations, their mechanisms of action, and contribution to disease, as well as discussing the clinical implications of such mutations.

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Section: Resultssupporting

confidence: 58%

Granulocyte Colony-Stimulating Factor Receptor Mutations in Myeloid Malignancy

Liongue

Ward

2014

Front. Oncol.

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“…3–6 Truncation mutations of the CSF3R have also been isolated in chronic leukemias, such as an adult with Ph+chronic myeloid leukemia as well as a child with SCN who developed chronic myelomonocytic leukemia and monosomy 7. 7,8 A leukemogenic role for variant GCSFR is supported by the recent report that five distinct CSF3R mutations emerged over two decades in a patient with SCN who developed secondary MDS/AML. 9 …”

Section: Introductionmentioning

confidence: 94%

Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition

et al. 2013

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Granulocyte colony-stimulating factor (GCSF) drives the production of myeloid progenitor and precursor cells toward neutrophils via the GCSF receptor (GCSFR, gene name CSF3R). Children with severe congenital neutropenia chronically receive pharmacologic doses of GCSF, and ~30% will develop myelodysplasia/acute myeloid leukemia (AML) associated with GCSFR truncation mutations. In addition to mutations, multiple isoforms of CSF3R have also been reported. We found elevated expression of the alternatively spliced isoform, class IV CSF3R in adult myelodysplastic syndrome/AML patients. Aside from its association with monosomy 7 and higher rates of relapse in pediatric AML patients, little is known about the biology of the class IV isoform. We found developmental regulation of CSF3R isoforms with the class IV expression more representative of a progenitor cell stage. Striking differences were found in phosphoprotein signaling involving Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and cell cycle gene expression. Enhanced proliferation by class IV GCSFR was associated with diminished STAT3 and STAT5 activation, yet showed sensitivity to JAK2 inhibitors. Alterations in the C-terminal domain of the GCSFR result in leukemic properties of enhanced growth, impaired differentiation and resistance to apoptosis, suggesting that they can behave as oncogenic drivers, sensitive to JAK2 inhibition.

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“…Moreover, in their report, patients who required more than 8 µg/kg per day of G-CSF had a higher cumulative incidence of leukemia (40%) after 10 years compared to 11% in responsive patients. AML is the predominant subtype of leukemia documented in those patients; yet ALL, CMML, and bi-phenotypic leukemia have also been reported [10,11]. Genetic abnormalities demonstrated in CN patients who have developed leukemia included monosomy 7, RAS mutations, trisomy 21, or G-CSF-receptor mutations.…”

Section: Severe Congenital Neutropeniamentioning

confidence: 94%

Hematopoetic Stem Cell Transplantation in Neutrophil Disorders: Severe Congenital Neutropenia, Leukocyte Adhesion Deficiency and Chronic Granulomatous Disease

Elhasid¹,

Rowe²

2009

Clinic Rev Allerg Immunol

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Until further progress will occur in the field of gene therapy, the only curative treatment available in severe congenital neutropenia, leukocyte adhesion deficiency, and chronic granulomatous disease is allogeneic hematopoietic stem cell transplantation (HSCT). This review summarizes the current data regarding indications for transplantation in each disease, treatment results using related and unrelated donors, as well as toxicity of HSCT in the above diseases.

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An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia

Cited by 31 publications

References 36 publications

Granulocyte Colony-Stimulating Factor Receptor Mutations in Myeloid Malignancy

Granulocyte Colony-Stimulating Factor Receptor Mutations in Myeloid Malignancy

Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition

Hematopoetic Stem Cell Transplantation in Neutrophil Disorders: Severe Congenital Neutropenia, Leukocyte Adhesion Deficiency and Chronic Granulomatous Disease

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