HAEM5:Acute myeloid leukaemia with NPM1 mutation: Difference between revisions

Anemia, thrombocytopenia, high white blood cell and platelet counts

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==Sites of Involvement==

Rare gene fusions involving ''NPM1'' genes (NPM1-MLF1 and NPM1–HAUS1) have been reported in patients with AML and are associated with cytoplasmic accumulation of NPM1<ref name=":2">{{Cite journal|last=Woolthuis|first=Carolien M.|last2=Mulder|first2=André B.|last3=Verkaik-Schakel|first3=Rikst Nynke|last4=Rosati|first4=Stefano|last5=Diepstra|first5=Arjan|last6=van den Berg|first6=Eva|last7=Schuringa|first7=Jan Jacob|last8=Vellenga|first8=Edo|last9=Kluin|first9=Philip M.|date=2013|title=A single center analysis of nucleophosmin in acute myeloid leukemia: value of combining immunohistochemistry with molecular mutation analysis|url=https://www.ncbi.nlm.nih.gov/pubmed/23716555|journal=Haematologica|volume=98|issue=10|pages=1532–1538|doi=10.3324/haematol.2012.079806|issn=1592-8721|pmc=3789457|pmid=23716555}}</ref><ref>{{Cite journal|last=Campregher|first=Paulo Vidal|last2=de Oliveira Pereira|first2=Welbert|last3=Lisboa|first3=Bianca|last4=Puga|first4=Renato|last5=Deolinda|first5=Elvira Rodrigues Pereira Velloso|last6=Helman|first6=Ricardo|last7=Marti|first7=Luciana Cavalheiro|last8=Guerra|first8=João Carlos Campos|last9=Manola|first9=Kalliopi N.|date=2016|title=A novel mechanism of NPM1 cytoplasmic localization in acute myeloid leukemia: the recurrent gene fusion NPM1-HAUS1|url=https://www.ncbi.nlm.nih.gov/pubmed/27036161|journal=Haematologica|volume=101|issue=7|pages=e287–290|doi=10.3324/haematol.2015.137364|issn=1592-8721|pmc=5004474|pmid=27036161}}</ref><ref name=":3">{{Cite journal|last=Falini|first=B.|last2=Bigerna|first2=B.|last3=Pucciarini|first3=A.|last4=Tiacci|first4=E.|last5=Mecucci|first5=C.|last6=Morris|first6=S. W.|last7=Bolli|first7=N.|last8=Rosati|first8=R.|last9=Hanissian|first9=S.|date=2006|title=Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML|url=https://www.ncbi.nlm.nih.gov/pubmed/16341033|journal=Leukemia|volume=20|issue=2|pages=368–371|doi=10.1038/sj.leu.2404068|issn=0887-6924|pmid=16341033}}</ref>.

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

*Diagnosis based on identification of genetic lesion of NPM1 by immunohistochemical and /or molecular testing.

*Minimal residual disease (MRD) monitoring of AML patients after chemotherapy provides important prognostic information<ref>{{Cite journal|last=Grimwade|first=David|last2=Freeman|first2=Sylvie D.|date=2014|title=Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "prime time"?|url=https://www.ncbi.nlm.nih.gov/pubmed/25049280|journal=Blood|volume=124|issue=23|pages=3345–3355|doi=10.1182/blood-2014-05-577593|issn=1528-0020|pmid=25049280}}</ref><ref>{{Cite journal|last=Hourigan|first=Christopher S.|last2=Karp|first2=Judith E.|date=2013|title=Minimal residual disease in acute myeloid leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23799371|journal=Nature Reviews. Clinical Oncology|volume=10|issue=8|pages=460–471|doi=10.1038/nrclinonc.2013.100|issn=1759-4782|pmc=4163748|pmid=23799371}}</ref>. Because ''NPM1'' mutations are very stable over the course of disease, they are an excellent marker for monitoring minimal residual disease (MRD) for ''NPM1'' mutated AML patients<ref name=":3" /><ref>{{Cite journal|last=Falini|first=B.|last2=Bolli|first2=N.|last3=Liso|first3=A.|last4=Martelli|first4=M. P.|last5=Mannucci|first5=R.|last6=Pileri|first6=S.|last7=Nicoletti|first7=I.|date=2009|title=Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications|url=https://www.ncbi.nlm.nih.gov/pubmed/19516275|journal=Leukemia|volume=23|issue=10|pages=1731–1743|doi=10.1038/leu.2009.124|issn=1476-5551|pmid=19516275}}</ref>. Indeed, several studies have suggested that MRD accessed by ''NPM1'' mutation level using PCR-based methods is a strong independent predictor of higher relapse risk<ref name=":7" /><ref>{{Cite journal|last=Ivey|first=Adam|last2=Hills|first2=Robert K.|last3=Simpson|first3=Michael A.|last4=Jovanovic|first4=Jelena V.|last5=Gilkes|first5=Amanda|last6=Grech|first6=Angela|last7=Patel|first7=Yashma|last8=Bhudia|first8=Neesa|last9=Farah|first9=Hassan|date=2016|title=Assessment of Minimal Residual Disease in Standard-Risk AML|url=https://www.ncbi.nlm.nih.gov/pubmed/26789727|journal=The New England Journal of Medicine|volume=374|issue=5|pages=422–433|doi=10.1056/NEJMoa1507471|issn=1533-4406|pmid=26789727}}</ref>.

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

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==Characteristic Chromosomal Patterns==

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trisomy 8, deletion 9q

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==Gene Mutations (SNV / INDEL)==

*Studies investigating the methods by which ''NPM1'' mutations lead to leukemogenesis show that ''NPM1'' mutation alone is not sufficient to cause AML<ref name=":4">{{Cite journal|last=Heath|first=E. M.|last2=Chan|first2=S. M.|last3=Minden|first3=M. D.|last4=Murphy|first4=T.|last5=Shlush|first5=L. I.|last6=Schimmer|first6=A. D.|date=2017|title=Biological and clinical consequences of NPM1 mutations in AML|url=https://www.ncbi.nlm.nih.gov/pubmed/28111462|journal=Leukemia|volume=31|issue=4|pages=798–807|doi=10.1038/leu.2017.30|issn=1476-5551|pmid=28111462}}</ref>.

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==Epigenomic Alterations==

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*The NPM1 gene encodes nucleophosmin (NPM), which is a multifunctional protein that shuttles between the nucleus and the cytoplasm, and binds many partners in distinct cellular compartments. It is involved in many cellular processes including ribosome biogenesis, maintenance of genomic stability and regulation of cellular proliferation.

*Mutations in ''NPM1'' represent a distinct entity in the World Health Organization (WHO) classification and commonly indicate a better risk prognosis<ref name=":4" />. Predominantly, observed ''NPM1'' variants are sited in exon 12 and cause a frameshift in the C-terminal domain, affecting one or both of the key tryptophan residues in the domain. Such ''NPM1'' mutations result in a ‘functionally stronger’ nuclear export than nuclear import signal (compared to wild-type NPM1) and thus there is cytoplasmic localization of the protein – ‘cytoplasmic NPM1’ (NPM1c)<ref name=":4" /><ref name=":6" />.  See Figure 3 in <ref name=":4" />. NPM1c sequesters ARF to the cytoplasm; however, unlike the ARF-NPM1 complex in the nucleolus, NPM1c is unable to stabilize ARF in the cytoplasm and consequently ARF becomes unstable and degrades<ref>{{Cite journal|last=Colombo|first=Emanuela|last2=Martinelli|first2=Paola|last3=Zamponi|first3=Raffaella|last4=Shing|first4=Danielle C.|last5=Bonetti|first5=Paola|last6=Luzi|first6=Lucilla|last7=Volorio|first7=Sara|last8=Bernard|first8=Loris|last9=Pruneri|first9=Giancarlo|date=2006|title=Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant|url=https://www.ncbi.nlm.nih.gov/pubmed/16540653|journal=Cancer Research|volume=66|issue=6|pages=3044–3050|doi=10.1158/0008-5472.CAN-05-2378|issn=0008-5472|pmid=16540653}}</ref>. Without ARF, there is lack of MDM2 inhibition, leading to p53 inactivation by MDM2 and the loss of growth inhibition by p53<ref name=":4" />. In the context of ''NPM1'' mutations, NPM1 haploinsufficiency results in uncontrolled centrosome duplication and consequently supernumerary centrosomes (a potential mechanism for tumor development)<ref>{{Cite journal|last=Sportoletti|first=Paolo|last2=Grisendi|first2=Silvia|last3=Majid|first3=Samia M.|last4=Cheng|first4=Ke|last5=Clohessy|first5=John G.|last6=Viale|first6=Agnes|last7=Teruya-Feldstein|first7=Julie|last8=Pandolfi|first8=Pier Paolo|date=2008|title=Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse|url=https://www.ncbi.nlm.nih.gov/pubmed/18212245|journal=Blood|volume=111|issue=7|pages=3859–3862|doi=10.1182/blood-2007-06-098251|issn=0006-4971|pmc=2275037|pmid=18212245}}</ref>. The loss of NPM1 function leads to activation of Myc oncogene (increased oncogene levels), promoting growth and cell proliferation. As expected, in the cytoplasm, NPM1c inhibits caspase-6/-8, promoting growth<ref name=":4" />.

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==Genetic Diagnostic Testing Methods==