HAEM5:Chronic neutrophilic leukaemia: Difference between revisions

{{DISPLAYTITLE:Chronic neutrophilic leukaemia}}

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==Primary Author(s)*==

==Clinical Features==

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|'''Signs and Symptoms'''

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|'''Laboratory Findings'''

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Most patients are asymptomatic, but sometimes present with fatigue. Constitutional symptoms may be present at diagnosis, including weight loss, and night sweats. Sometimes bruising, pruritus, or gout. A common clinical manifestation is hepatosplenomegaly.  

==Immunophenotype==

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!Finding!!Marker

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There is no specific immunophenotype.<ref name=":0" />

!Notes

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|Yes

|No

|Yes

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

CNL is by definition Philadelphia chromosome negative (BCR/ABL1-negative).<ref name=":0" />  

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* Chromosomal Rearrangements (Gene Fusions)

* Individual Region Genomic Gain/Loss/LOH

==Individual Region Genomic Gain / Loss / LOH==

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!Notes

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7

chr7:1- 159,335,973 [hg38]

chr7

|Yes

|No

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

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8

chr8:1-145,138,636 [hg38]

chr8

|No

|No

Common recurrent secondary finding for t(8;21) (add reference).

==Characteristic Chromosomal Patterns==

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!Notes

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Co-deletion of 1p and 18q

|No

|No

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

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Karyotypic abnormalities occur in ~10% of cases while 90% of CNL cases demonstrate a normal karyotype.<ref name=":0" /><ref name=":1" />  There are no diagnostic gains, chromosome losses or losses of heterozygosity (LOH) associated with CNL.   

==Gene Mutations (SNV / INDEL)==

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!Notes

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EGFR; Exon 20 mutations

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<br />

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CNL has been strongly associated with mutations in ''CSF3R''.<ref name=":3" /><ref name=":7" />  Two types of ''CSF3R'' mutations have been described.  The first is a missense mutation involving the juxta-membrane region (e.g. T618I, the most common ''CSF3R'' mutation in CNL).  The other results in a nonsense or frameshift mutation leading to a truncated protein and subsequent loss of the C-terminus tail region (e.g. ''CSF3R'' D771fs, S783 fs, Y752X, and W791Z).<ref name=":3" /><ref name=":7" />   CNL can also be associated with several genes involved in mRNA splicing, epigenetic modifications, and signaling proteins.   Notably, mutations in ''SETBP1'' and ''ASXL1'' have been described as frequent co-occurrences in association with mutated ''CSF3R''.<ref name=":7" /><ref name=":8" />  Less frequently, concurrent ''JAK2'' mutations have also been identified with mutated ''CSF3R''.<ref name=":0" /><ref name=":3" /><ref name=":7" /><ref name=":8" />

==Genes and Main Pathways Involved==

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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

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Colony-stimulating factor 3 receptor (''CSF3R'') is a gene located on chromosome 1p34.3 encoding the cytokine receptor for granulocyte colony-stimulating factor (G-CSF) or otherwise known as colony-stimulating factor 3 (CSF 3). Its binding activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Ras/Raf/MAP kinases, and PI3K/Akt pathways; ''CSF3R'' has been shown to signal through the JAK–STAT pathway, the nonreceptor tyrosine kinase ''SYK'', and the SRC family kinase ''LYN''.<ref>{{Cite journal|last=Corey|first=S. J.|last2=Dombrosky-Ferlan|first2=P. M.|last3=Zuo|first3=S.|last4=Krohn|first4=E.|last5=Donnenberg|first5=A. D.|last6=Zorich|first6=P.|last7=Romero|first7=G.|last8=Takata|first8=M.|last9=Kurosaki|first9=T.|date=1998-02-06|title=Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor|url=https://pubmed.ncbi.nlm.nih.gov/9452436|journal=The Journal of Biological Chemistry|volume=273|issue=6|pages=3230–3235|doi=10.1074/jbc.273.6.3230|issn=0021-9258|pmid=9452436}}</ref><ref>{{Cite journal|last=Corey|first=S. J.|last2=Burkhardt|first2=A. L.|last3=Bolen|first3=J. B.|last4=Geahlen|first4=R. L.|last5=Tkatch|first5=L. S.|last6=Tweardy|first6=D. J.|date=1994-05-24|title=Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases|url=https://pubmed.ncbi.nlm.nih.gov/8197119|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=91|issue=11|pages=4683–4687|doi=10.1073/pnas.91.11.4683|issn=0027-8424|pmc=PMC43852|pmid=8197119}}</ref>  In bone marrow it stimulates granulopoesis by inducing proliferation and differentiation of precursor cells into mature granulocytes.<ref name=":1" />