Chronic neutrophilic leukemia pathophysiology: Difference between revisions
Created page with "__NOTOC__ {{Chronic neutrophilic leukemia}} {{CMG}}; {{AE}} ==Overview== The exact pathogenesis of [disease name] is not fully understood. OR It is thought that [disease n..." |
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==Pathophysiology== | ==Pathophysiology== | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
*It is understood that clonality has role in pathogenesis of CNL. | |||
*The cytogenetic abnormalities may seen as: | |||
*It is understood that | |||
*[Pathogen name] is usually transmitted via the [transmission route] route to the human host. | *[Pathogen name] is usually transmitted via the [transmission route] route to the human host. | ||
*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell. | *Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell. | ||
| Line 44: | Line 40: | ||
*The progression to [disease name] usually involves the [molecular pathway]. | *The progression to [disease name] usually involves the [molecular pathway]. | ||
*The pathophysiology of [disease/malignancy] depends on the histological subtype. | *The pathophysiology of [disease/malignancy] depends on the histological subtype. | ||
Evidence for clonality in CNL was initially supported by the finding of a monoclonal methylation pattern of the Xlinked hypoxanthine phosphoribosyl transferase (HPRT) gene in a patient with CNL. Other groups subsequently demonstrated the clonal nature of the leukemic neutrophils in CNL using HUMARA clonality studies84 and fluorescent in situ hybridization (FISH)85. Although the majority of patients with CNL display normal cytogenetics at diagnosis the demonstration of non-specific cytogenetic abnormalities in a proportion of CNL patients served as later proof of clonality. A report by Didonato et al. was the first to demonstrate cytogenetic aberrations in the form of trisomy 9 and a partial deletion of the long arms of chromosome 20 in a patient with suspected CNL86. Ensuing reports confirmed the occurrence of cytogenetic abnormalities in a minority of CNL patients at diagnosis and/or during clonal evolution6,12,87. In Reilly’s 2002 review, 37% of CNL cases presented abnormal cytogenetics consisting primarily of trisomy 8, trisomy 21, deletion 11q, and deletion 20q6. Subsequently one of the largest CNL case series (total of 40 CNL patients) identified cytogenetic abnormalities in 13 of 40 patients (32.5%)12. These aberrations were detected at baseline in 20% of patients and during clonal evolution in the remaining 12.5% and included deletion 20q, trisomy 21, deletion 11q, and deletion 12p12. Though the most common chromosomal lesions in CNL consist of trisomy 8 and deletion 20q, observed either at diagnosis or at the time of clonal evolution18, multiple additional abnormalities have been described including tetraploidy 21, trisomies 7, 8, and 9, translocation 1;20, deletion Y, deletion 6, add 5p, deletion 15, and monosomy 288, and are considered non-specific, yet non-random findings in myeloid neoplasms89. In rare cases, detection of a well-known MPN molecular marker such as JAK2V617F may also serve to establish clonality12 | |||
Discovery of the CSF3R mutation in 2013 has expanded our understanding of the molecular pathogenesis of CNL.16,23 CSF3R encodes the receptor for neutrophilic growth factor CSF3,30 and it exploits the Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway for signal transduction, among others.31 Two classes of CSF3R mutations are observed in CNL-membrane-proximal mutations and truncation mutations (Table 2). The truncation mutations prompt the loss of a di-leucine internalization motif in the cytoplasmic domain of the CSF3R receptor and the binding site for suppressor of cytokine signaling 3, resulting in decreased lysosomal trafficking of the receptor. This in turn augments the cell-surface expression of the receptor, thus conferring ligand hypersensitivity and ensuing neutrophil proliferation. In contrast, the membrane-proximal mutations cause ligandindependent homodimerization, inducing autonomous cell proliferation. | |||
The 2 CSF3R mutation classes do not merely differ in their transforming capacity but also in downstream signal activation. In vitro studies have revealed that membrane-proximal mutations (T615A, T618I, and T640N) result in dysregulated JAK2/STAT3 signaling, and truncation mutations (D771fs, S783fs, Y752X, and W791X) result in dysregulation of SRC family tyrosine kinase nonreceptor 2 (TNK2 kinases),33 thus bestowing sensitivity to JAK inhibitor ruxolitinib and SRC kinase inhibitor dasatinib, respectively 23,34 Truncation mutations engender ligand-dependent receptor activation in a Ba/f3 cell line as opposed to the membraneproximal mutations. Furthermore, truncation mutations necessitate the presence of cooperating mutations to realize their oncogenic potential.23,35 Additionally, 33% of patients manifest dual truncation and membrane-proximal mutations on the same allele,23 and display enhanced leukemogenicity through activation of mitogenactivated protein kinase (MAPK) signaling pathway. These compound mutants are characteristically impervious to ruxolitinib or dasatinib, given their reliance on MAPK signaling. | |||
==Genetics== | ==Genetics== | ||
Revision as of 18:35, 14 January 2019
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Chronic neutrophilic leukemia Microchapters |
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Differentiating Chronic neutrophilic leukemia from other Diseases |
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Diagnosis |
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Treatment |
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Case Studies |
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Chronic neutrophilic leukemia pathophysiology On the Web |
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American Roentgen Ray Society Images of Chronic neutrophilic leukemia pathophysiology |
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Directions to Hospitals Treating Chronic neutrophilic leukemia |
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Risk calculators and risk factors for Chronic neutrophilic leukemia pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
The exact pathogenesis of [disease name] is not fully understood.
OR
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
OR
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
OR
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
OR
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
OR
The progression to [disease name] usually involves the [molecular pathway].
OR
The pathophysiology of [disease/malignancy] depends on the histological subtype.
Pathophysiology
Pathogenesis
- It is understood that clonality has role in pathogenesis of CNL.
- The cytogenetic abnormalities may seen as:
- [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
- Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
- [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
- The progression to [disease name] usually involves the [molecular pathway].
- The pathophysiology of [disease/malignancy] depends on the histological subtype.
Evidence for clonality in CNL was initially supported by the finding of a monoclonal methylation pattern of the Xlinked hypoxanthine phosphoribosyl transferase (HPRT) gene in a patient with CNL. Other groups subsequently demonstrated the clonal nature of the leukemic neutrophils in CNL using HUMARA clonality studies84 and fluorescent in situ hybridization (FISH)85. Although the majority of patients with CNL display normal cytogenetics at diagnosis the demonstration of non-specific cytogenetic abnormalities in a proportion of CNL patients served as later proof of clonality. A report by Didonato et al. was the first to demonstrate cytogenetic aberrations in the form of trisomy 9 and a partial deletion of the long arms of chromosome 20 in a patient with suspected CNL86. Ensuing reports confirmed the occurrence of cytogenetic abnormalities in a minority of CNL patients at diagnosis and/or during clonal evolution6,12,87. In Reilly’s 2002 review, 37% of CNL cases presented abnormal cytogenetics consisting primarily of trisomy 8, trisomy 21, deletion 11q, and deletion 20q6. Subsequently one of the largest CNL case series (total of 40 CNL patients) identified cytogenetic abnormalities in 13 of 40 patients (32.5%)12. These aberrations were detected at baseline in 20% of patients and during clonal evolution in the remaining 12.5% and included deletion 20q, trisomy 21, deletion 11q, and deletion 12p12. Though the most common chromosomal lesions in CNL consist of trisomy 8 and deletion 20q, observed either at diagnosis or at the time of clonal evolution18, multiple additional abnormalities have been described including tetraploidy 21, trisomies 7, 8, and 9, translocation 1;20, deletion Y, deletion 6, add 5p, deletion 15, and monosomy 288, and are considered non-specific, yet non-random findings in myeloid neoplasms89. In rare cases, detection of a well-known MPN molecular marker such as JAK2V617F may also serve to establish clonality12
Discovery of the CSF3R mutation in 2013 has expanded our understanding of the molecular pathogenesis of CNL.16,23 CSF3R encodes the receptor for neutrophilic growth factor CSF3,30 and it exploits the Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway for signal transduction, among others.31 Two classes of CSF3R mutations are observed in CNL-membrane-proximal mutations and truncation mutations (Table 2). The truncation mutations prompt the loss of a di-leucine internalization motif in the cytoplasmic domain of the CSF3R receptor and the binding site for suppressor of cytokine signaling 3, resulting in decreased lysosomal trafficking of the receptor. This in turn augments the cell-surface expression of the receptor, thus conferring ligand hypersensitivity and ensuing neutrophil proliferation. In contrast, the membrane-proximal mutations cause ligandindependent homodimerization, inducing autonomous cell proliferation.
The 2 CSF3R mutation classes do not merely differ in their transforming capacity but also in downstream signal activation. In vitro studies have revealed that membrane-proximal mutations (T615A, T618I, and T640N) result in dysregulated JAK2/STAT3 signaling, and truncation mutations (D771fs, S783fs, Y752X, and W791X) result in dysregulation of SRC family tyrosine kinase nonreceptor 2 (TNK2 kinases),33 thus bestowing sensitivity to JAK inhibitor ruxolitinib and SRC kinase inhibitor dasatinib, respectively 23,34 Truncation mutations engender ligand-dependent receptor activation in a Ba/f3 cell line as opposed to the membraneproximal mutations. Furthermore, truncation mutations necessitate the presence of cooperating mutations to realize their oncogenic potential.23,35 Additionally, 33% of patients manifest dual truncation and membrane-proximal mutations on the same allele,23 and display enhanced leukemogenicity through activation of mitogenactivated protein kinase (MAPK) signaling pathway. These compound mutants are characteristically impervious to ruxolitinib or dasatinib, given their reliance on MAPK signaling.
Genetics
[Disease name] is transmitted in [mode of genetic transmission] pattern.
OR
Genes involved in the pathogenesis of [disease name] include:
- [Gene1]
- [Gene2]
- [Gene3]
OR
The development of [disease name] is the result of multiple genetic mutations such as:
- [Mutation 1]
- [Mutation 2]
- [Mutation 3]
Associated Conditions
Conditions associated with [disease name] include:
- [Condition 1]
- [Condition 2]
- [Condition 3]
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].