HAEM5:Chronic neutrophilic leukaemia: Difference between revisions

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.  

Blood analysis can show elevated values for LDH, leukocyte alkaline phosphatase (LAP), serum vitamin B12, and uric acid.

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==Sites of Involvement==

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

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==Chromosomal Rearrangements (Gene Fusions)==

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

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

CNL can progress to myeloma or blastic transformation to acute myeloid leukemia.<ref name=":1" />  It can also transform in other forms of MPN (PV or CMML). The presence of ''ASXL1'' as secondary mutation confers worse prognosis.<ref name=":0" /><ref name=":8">{{Cite journal|last=Ma|first=Elliott|last2=A|first2=Pardanani|last3=Ca|first3=Hanson|last4=Tl|first4=Lasho|last5=Cm|first5=Finke|last6=Aa|first6=Belachew|last7=A|first7=Tefferi|date=2015|title=ASXL1 mutations are frequent and prognostically detrimental in CSF3R-mutated chronic neutrophilic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/25850813/|language=en|pmid=25850813}}</ref>

The presenting features may be non-specific with organomegaly involving the liver, spleen or both, mucocutaneous bleeding, and bruising.<ref name=":0" />  The disease has a variable prognosis with some cases rapidly evolving<ref name=":6" /><ref>{{Cite journal|last=Zittoun|first=R.|last2=Réa|first2=D.|last3=Ngoc|first3=L. H.|last4=Ramond|first4=S.|date=1994-02|title=Chronic neutrophilic leukemia. A study of four cases|url=https://pubmed.ncbi.nlm.nih.gov/8148416|journal=Annals of Hematology|volume=68|issue=2|pages=55–60|doi=10.1007/BF01715131|issn=0939-5555|pmid=8148416}}</ref>; others may have an indolent course spanning decades.<ref>{{Cite journal|last=Uppal|first=Guldeep|last2=Gong|first2=Jerald|date=2015-09|title=Chronic neutrophilic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/26082513|journal=Journal of Clinical Pathology|volume=68|issue=9|pages=680–684|doi=10.1136/jclinpath-2015-203060|issn=1472-4146|pmid=26082513}}</ref>  Survival is variable, overall mean survival being between 21-30 months.

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

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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.   

Sometimes a complex karyotype is present.

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==Gene Mutations (SNV / INDEL)==

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" />

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==Epigenomic Alterations==

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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" />

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==Genetic Diagnostic Testing Methods==