Limits...
Chronic neutrophilic leukemia: a clinical perspective.

Menezes J, Cigudosa JC - Onco Targets Ther (2015)

Bottom Line: However, this scenario changed with the identification of oncogenic mutations in the CSF3R gene in approximately 83% of WHO-defined and no monoclonal gammopathy-associated CNL patients.In addition to CSF3R mutations, other genetic alterations have been found, notably mutations in SETBP1, which may be used as prognostic markers to guide therapeutic decisions.In this review, we discuss the new genetic alterations recently found in CNL and the clinical perspectives in its diagnosis and treatment.

View Article: PubMed Central - PubMed

Affiliation: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre - CNIO, Madrid, Spain.

ABSTRACT
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that includes only 150 patients described to date meeting the latest World Health Organization (WHO) criteria and the recently reported CSF3R mutations. The diagnosis is based on morphological criteria of granulocytic cells and the exclusion of genetic drivers that are known to occur in others MPNs, such as BCR-ABL1, PDGFRA/B, or FGFR1 rearrangements. However, this scenario changed with the identification of oncogenic mutations in the CSF3R gene in approximately 83% of WHO-defined and no monoclonal gammopathy-associated CNL patients. CSF3R T618I is a highly specific molecular marker for CNL that is sensitive to inhibition in vitro and in vivo by currently approved protein kinase inhibitors. In addition to CSF3R mutations, other genetic alterations have been found, notably mutations in SETBP1, which may be used as prognostic markers to guide therapeutic decisions. These findings will help to understand the pathogenesis of CNL and greatly impact the clinical management of this disease. In this review, we discuss the new genetic alterations recently found in CNL and the clinical perspectives in its diagnosis and treatment. Fortunately, since the diagnosis of CNL is not based on exclusion anymore, the molecular characterization of the CSF3R gene must be included in the WHO criteria for CNL diagnosis.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of CSF3R mutations and pathways activation.Notes:CSF3R is known to signal downstream through both JAK and SRC tyrosine kinase pathways, and the two classes of CSF3R mutations exhibit different downstream signaling and kinase inhibitor sensitivities. CSF3R truncation mutations operate predominantly through SRC kinases and exhibit drug sensitivity to SRC kinase inhibitors, such as dasatinib. In contrast, CSF3R membrane proximal mutations strongly activate the JAK/signal transducer and activator of transcription pathways, and are sensitive to JAK kinase inhibitors, such as ruxolitinib.Abbreviation: JAK, Janus kinase.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4562747&req=5

f2-ott-8-2383: Schematic representation of CSF3R mutations and pathways activation.Notes:CSF3R is known to signal downstream through both JAK and SRC tyrosine kinase pathways, and the two classes of CSF3R mutations exhibit different downstream signaling and kinase inhibitor sensitivities. CSF3R truncation mutations operate predominantly through SRC kinases and exhibit drug sensitivity to SRC kinase inhibitors, such as dasatinib. In contrast, CSF3R membrane proximal mutations strongly activate the JAK/signal transducer and activator of transcription pathways, and are sensitive to JAK kinase inhibitors, such as ruxolitinib.Abbreviation: JAK, Janus kinase.

Mentions: SETBP1 interacts with SET, a negative regulator of the tumor suppressor protein phosphatase 2A (PP2A).36SETBP1 protects SET from protease cleavage, thus increasing the amount of SET available to repress the activity of PP2A.37 In AML, SETBP1 overexpression is significantly associated with reduced survival, indicating that SETBP1 may be relevant to leukemia oncogenesis.37SETBP1 mutations were recently identified in 25% of aCML patients, and in lower frequencies in unclassified MDS/MPN (10%),20 CMML (14.5%), and AML (<1%),38 but no mutation was identified in lymphoid leukemia or solid tumors.20SETBP1 mutations in aCML were associated with a higher white blood cells (WBC) count at diagnosis and poorer survival.20 The prevalence of SETBP1 mutations in CNL coexpressing CSF3R T618I is 24% (Figure 2).2 Although these cases showed a trend to reduce survival, the analysis is limited by the small number of cases. Further follow-up studies are necessary to confirm these findings so that SETBP1 could be used as a prognostic marker to guide therapeutic decisions.


Chronic neutrophilic leukemia: a clinical perspective.

Menezes J, Cigudosa JC - Onco Targets Ther (2015)

Schematic representation of CSF3R mutations and pathways activation.Notes:CSF3R is known to signal downstream through both JAK and SRC tyrosine kinase pathways, and the two classes of CSF3R mutations exhibit different downstream signaling and kinase inhibitor sensitivities. CSF3R truncation mutations operate predominantly through SRC kinases and exhibit drug sensitivity to SRC kinase inhibitors, such as dasatinib. In contrast, CSF3R membrane proximal mutations strongly activate the JAK/signal transducer and activator of transcription pathways, and are sensitive to JAK kinase inhibitors, such as ruxolitinib.Abbreviation: JAK, Janus kinase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562747&req=5

f2-ott-8-2383: Schematic representation of CSF3R mutations and pathways activation.Notes:CSF3R is known to signal downstream through both JAK and SRC tyrosine kinase pathways, and the two classes of CSF3R mutations exhibit different downstream signaling and kinase inhibitor sensitivities. CSF3R truncation mutations operate predominantly through SRC kinases and exhibit drug sensitivity to SRC kinase inhibitors, such as dasatinib. In contrast, CSF3R membrane proximal mutations strongly activate the JAK/signal transducer and activator of transcription pathways, and are sensitive to JAK kinase inhibitors, such as ruxolitinib.Abbreviation: JAK, Janus kinase.
Mentions: SETBP1 interacts with SET, a negative regulator of the tumor suppressor protein phosphatase 2A (PP2A).36SETBP1 protects SET from protease cleavage, thus increasing the amount of SET available to repress the activity of PP2A.37 In AML, SETBP1 overexpression is significantly associated with reduced survival, indicating that SETBP1 may be relevant to leukemia oncogenesis.37SETBP1 mutations were recently identified in 25% of aCML patients, and in lower frequencies in unclassified MDS/MPN (10%),20 CMML (14.5%), and AML (<1%),38 but no mutation was identified in lymphoid leukemia or solid tumors.20SETBP1 mutations in aCML were associated with a higher white blood cells (WBC) count at diagnosis and poorer survival.20 The prevalence of SETBP1 mutations in CNL coexpressing CSF3R T618I is 24% (Figure 2).2 Although these cases showed a trend to reduce survival, the analysis is limited by the small number of cases. Further follow-up studies are necessary to confirm these findings so that SETBP1 could be used as a prognostic marker to guide therapeutic decisions.

Bottom Line: However, this scenario changed with the identification of oncogenic mutations in the CSF3R gene in approximately 83% of WHO-defined and no monoclonal gammopathy-associated CNL patients.In addition to CSF3R mutations, other genetic alterations have been found, notably mutations in SETBP1, which may be used as prognostic markers to guide therapeutic decisions.In this review, we discuss the new genetic alterations recently found in CNL and the clinical perspectives in its diagnosis and treatment.

View Article: PubMed Central - PubMed

Affiliation: Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre - CNIO, Madrid, Spain.

ABSTRACT
Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that includes only 150 patients described to date meeting the latest World Health Organization (WHO) criteria and the recently reported CSF3R mutations. The diagnosis is based on morphological criteria of granulocytic cells and the exclusion of genetic drivers that are known to occur in others MPNs, such as BCR-ABL1, PDGFRA/B, or FGFR1 rearrangements. However, this scenario changed with the identification of oncogenic mutations in the CSF3R gene in approximately 83% of WHO-defined and no monoclonal gammopathy-associated CNL patients. CSF3R T618I is a highly specific molecular marker for CNL that is sensitive to inhibition in vitro and in vivo by currently approved protein kinase inhibitors. In addition to CSF3R mutations, other genetic alterations have been found, notably mutations in SETBP1, which may be used as prognostic markers to guide therapeutic decisions. These findings will help to understand the pathogenesis of CNL and greatly impact the clinical management of this disease. In this review, we discuss the new genetic alterations recently found in CNL and the clinical perspectives in its diagnosis and treatment. Fortunately, since the diagnosis of CNL is not based on exclusion anymore, the molecular characterization of the CSF3R gene must be included in the WHO criteria for CNL diagnosis.

No MeSH data available.


Related in: MedlinePlus