Bailey.Glen: Created page with "==Primary Author(s)*== Xinjie Xu, PhD, FACMG TOC ==Cancer Category/Type== Acute Myeloid Leukemia (AML) ==Cancer Sub-Classification / Subtype== Acute myeloid leukaemia..."

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Created page with "==Primary Author(s)*== Xinjie Xu, PhD, FACMG __TOC__ ==Cancer Category/Type== Acute Myeloid Leukemia (AML) ==Cancer Sub-Classification / Subtype== Acute myeloid leukaemia..."

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==Primary Author(s)*==
Xinjie Xu, PhD, FACMG

__TOC__

==Cancer Category/Type==

Acute Myeloid Leukemia (AML)

==Cancer Sub-Classification / Subtype==

Acute myeloid leukaemia (AML) with mutated NPM1

==Definition / Description of Disease==

NPM1 mutated AML is a distinct disease entity in the 2016 World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia.

==Synonyms / Terminology==

AML with cytoplasmic nucleophosmin

==Epidemiology / Prevalence==
Somatic mutations of ''NPM1'' are observed in 22-18% of patients with ''de novo'' acute myeloid leukemia (AML), with a higher incidence (50-60%) in cytogenetically normal AML, making them one of the most frequent genetic alterations in AML<ref>{{Cite journal|last=Courville|first=Elizabeth L.|last2=Wu|first2=Yue|last3=Kourda|first3=Jihen|last4=Roth|first4=Christine G.|last5=Brockmann|first5=Jillian|last6=Muzikansky|first6=Alona|last7=Fathi|first7=Amir T.|last8=de Leval|first8=Laurence|last9=Orazi|first9=Attilio|date=2013|title=Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/23307061|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=26|issue=6|pages=751–761|doi=10.1038/modpathol.2012.218|issn=1530-0285|pmid=23307061}}</ref><ref name=":0">{{Cite journal|last=Falini|first=Brunangelo|last2=Sportoletti|first2=Paolo|last3=Martelli|first3=Maria Paola|date=2009|title=Acute myeloid leukemia with mutated NPM1: diagnosis, prognosis and therapeutic perspectives|url=https://www.ncbi.nlm.nih.gov/pubmed/19770764|journal=Current Opinion in Oncology|volume=21|issue=6|pages=573–581|doi=10.1097/CCO.0b013e3283313dfa|issn=1531-703X|pmid=19770764}}</ref><ref name=":1">{{Cite journal|last=Papaemmanuil|first=Elli|last2=Gerstung|first2=Moritz|last3=Bullinger|first3=Lars|last4=Gaidzik|first4=Verena I.|last5=Paschka|first5=Peter|last6=Roberts|first6=Nicola D.|last7=Potter|first7=Nicola E.|last8=Heuser|first8=Michael|last9=Thol|first9=Felicitas|date=2016|title=Genomic Classification and Prognosis in Acute Myeloid Leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27276561|journal=The New England Journal of Medicine|volume=374|issue=23|pages=2209–2221|doi=10.1056/NEJMoa1516192|issn=1533-4406|pmc=4979995|pmid=27276561}}</ref>.

The incidence of mutated ''NPM1'' is much lower in other myeloid malignancies (5-6% of patients with chronic myelomonocytic leukemia and 2-5% of patients with myelodysplastic syndrome), however, it appears to increase after leukemic transformation (17% of CMML patients that progressed to AML and 9% of MDS-AML patients)<ref>{{Cite journal|last=Bains|first=Ashish|last2=Luthra|first2=Rajyalakshmi|last3=Medeiros|first3=L. Jeffrey|last4=Zuo|first4=Zhuang|date=2011|title=FLT3 and NPM1 mutations in myelodysplastic syndromes: Frequency and potential value for predicting progression to acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/21173125|journal=American Journal of Clinical Pathology|volume=135|issue=1|pages=62–69|doi=10.1309/AJCPEI9XU8PYBCIO|issn=1943-7722|pmid=21173125}}</ref><ref>{{Cite journal|last=Caudill|first=Jonathan S. C.|last2=Sternberg|first2=Alexander J.|last3=Li|first3=Chin-Yang|last4=Tefferi|first4=Ayalew|last5=Lasho|first5=Terra L.|last6=Steensma|first6=David P.|date=2006|title=C-terminal nucleophosmin mutations are uncommon in chronic myeloid disorders|url=https://www.ncbi.nlm.nih.gov/pubmed/16704439|journal=British Journal of Haematology|volume=133|issue=6|pages=638–641|doi=10.1111/j.1365-2141.2006.06081.x|issn=0007-1048|pmid=16704439}}</ref><ref>{{Cite journal|last=Dicker|first=F.|last2=Haferlach|first2=C.|last3=Sundermann|first3=J.|last4=Wendland|first4=N.|last5=Weiss|first5=T.|last6=Kern|first6=W.|last7=Haferlach|first7=T.|last8=Schnittger|first8=S.|date=2010|title=Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML|url=https://www.ncbi.nlm.nih.gov/pubmed/20520634|journal=Leukemia|volume=24|issue=8|pages=1528–1532|doi=10.1038/leu.2010.124|issn=1476-5551|pmid=20520634}}</ref><ref>{{Cite journal|last=Ernst|first=Thomas|last2=Chase|first2=Andrew|last3=Zoi|first3=Katerina|last4=Waghorn|first4=Katherine|last5=Hidalgo-Curtis|first5=Claire|last6=Score|first6=Joannah|last7=Jones|first7=Amy|last8=Grand|first8=Francis|last9=Reiter|first9=Andreas|date=2010|title=Transcription factor mutations in myelodysplastic/myeloproliferative neoplasms|url=https://www.ncbi.nlm.nih.gov/pubmed/20421268|journal=Haematologica|volume=95|issue=9|pages=1473–1480|doi=10.3324/haematol.2010.021808|issn=1592-8721|pmc=2930947|pmid=20421268}}</ref><ref>{{Cite journal|last=Zhang|first=Yue|last2=Zhang|first2=Meirong|last3=Yang|first3=Lin|last4=Xiao|first4=Zhijian|date=2007|title=NPM1 mutations in myelodysplastic syndromes and acute myeloid leukemia with normal karyotype|url=https://www.ncbi.nlm.nih.gov/pubmed/16678898|journal=Leukemia Research|volume=31|issue=1|pages=109–111|doi=10.1016/j.leukres.2006.03.013|issn=0145-2126|pmid=16678898}}</ref>.

More common in females

==Clinical Features==
Anemia, thrombocytopenia, high white blood cell and platelet counts

==Sites of Involvement==

Bone marrow, gingiva, lymph nodes and skin

==Morphologic Features==

Strong association with [[acute myelomonocytic]] and [[monocytic leukemia]] wich often have NPM1 nutations.

NPM1 mutations are also found in in AML with or without maturation and in pure erythroid leukemia.

==Immunophenotype==

POSITIVE:High CD33, low CD13, KIT,CD123,CD110
NEGATIVE: HLA-DR

IHC detection of cytoplasmic NPM1 expression is predictive on molecular mutation, because the morphological changes/staining are the result of the mutation effects in the cells.
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||EXAMPLE CD1
|-
|Positive (subset)||EXAMPLE CD2
|-
|Negative (universal)||EXAMPLE CD3
|-
|Negative (subset)||EXAMPLE CD4
|}

==Chromosomal Rearrangements (Gene Fusions)==

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>.

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 5%
|-
|EXAMPLE t(8;21)(q22;q22)||EXAMPLE 5'RUNX1 / 3'RUNXT1||EXAMPLE der(8)||EXAMPLE 5%
|}

==Characteristic Chromosomal Aberrations / Patterns==

trisomy 8, deletion 9q

==Genomic Gain/Loss/LOH==

==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>.

*AML associated ''NPM1'' mutations are generally frame-shift alterations at codons Trp288 and Trp290 with the most common alterations being 4-bp insertions that disrupt the NPM nucleolar-localization signal and generate a leucine-rich nuclear export signal, thus leading to abnormal cytoplasmic accumulation of NPM. In addition, a small subset of AML cases with NPM cytoplasmic localization by immunohistochemical staining did not harbor detectable ''NPM1'' mutations<ref name=":2" />, raising the possibility of alternative mechanisms for ectopic NPM expression.

*In a study of 52 primary AML patients with cytoplasmic NPM1 (NPM1c), 98% of the subjects had exon 12 mutations; over 55 unique mutations have been identified in exon 12<ref name=":4" /><ref name=":5">{{Cite journal|last=Falini|first=Brunangelo|last2=Mecucci|first2=Cristina|last3=Tiacci|first3=Enrico|last4=Alcalay|first4=Myriam|last5=Rosati|first5=Roberto|last6=Pasqualucci|first6=Laura|last7=La Starza|first7=Roberta|last8=Diverio|first8=Daniela|last9=Colombo|first9=Emanuela|date=2005|title=Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype|url=https://www.ncbi.nlm.nih.gov/pubmed/15659725|journal=The New England Journal of Medicine|volume=352|issue=3|pages=254–266|doi=10.1056/NEJMoa041974|issn=1533-4406|pmid=15659725}}</ref>. Most mutations consist of a 4-base-pair insertion with >95% of mutations occurring between nucleotides 960 and 961 NM_002520<ref name=":5" />. The most common mutation (“type A”) involve duplication of TCTG (nucleotides 956-959 NM_002520), resulting in an insertion at position 960 NM_002520<ref name=":5" />. Type B and D mutations, which are also relatively common, both involve 4-base-pair insertions at position 960 NM_002520 [21]. ''NPM1'' mutations cause increased nuclear exporting of NPM1 protein, compared to wild-type NPM1, hence increased cytoplasmic localization of the protein – ‘cytoplasmic NPM1’ (NPM1c)<ref name=":4" /><ref name=":6">{{Cite journal|last=Falini|first=Brunangelo|last2=Martelli|first2=Maria Paola|last3=Bolli|first3=Niccolò|last4=Bonasso|first4=Rossella|last5=Ghia|first5=Emanuela|last6=Pallotta|first6=Maria Teresa|last7=Diverio|first7=Daniela|last8=Nicoletti|first8=Ildo|last9=Pacini|first9=Roberta|date=2006|title=Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/16720834|journal=Blood|volume=108|issue=6|pages=1999–2005|doi=10.1182/blood-2006-03-007013|issn=0006-4971|pmid=16720834}}</ref>.

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%
|}

===Other Mutations===

*In ''NPM1'' mutated AML, concurrent mutations have been found in ''DNMT3A'' (54%), ''NRAS'' (19%), ''TET2'' (16%) and ''PTPN11'' (15%)<ref name=":1" />.

*The most prominent of the complex gene interactions is between ''NPM1'', ''DNMT3A'' and ''FLT3''-ITD (internal tandem duplication). The co-occurrence of these various mutations have differing prognostic implications<ref name=":4" />.

{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||DNMT3A, TET2, IDH1, IDH2, FLT3-ITD
|-
|Secondary Mutations||Trisomy 8, del (9q)
|-
|Mutually Exclusive||other AML with recurrent genetic abnormalities
|}

==Epigenomics (Methylation)==

Put your text here

==Genes and Main Pathways Involved==

*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" />.

==Diagnostic Testing Methods==

Put your text here

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

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

*Mutated ''NPM1'' is associated with a favorable prognosis in AML patients who do not have FLT3-internal tandem duplication (FLT3-ITD) mutations and with normal karyotype<ref name=":0" /><ref name=":1" /><ref>{{Cite journal|last=Schnittger|first=S.|last2=Bacher|first2=U.|last3=Kern|first3=W.|last4=Alpermann|first4=T.|last5=Haferlach|first5=C.|last6=Haferlach|first6=T.|date=2011|title=Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/21537333|journal=Leukemia|volume=25|issue=8|pages=1297–1304|doi=10.1038/leu.2011.97|issn=1476-5551|pmid=21537333}}</ref><ref name=":7">{{Cite journal|last=Schnittger|first=Susanne|last2=Kern|first2=Wolfgang|last3=Tschulik|first3=Claudia|last4=Weiss|first4=Tamara|last5=Dicker|first5=Frank|last6=Falini|first6=Brunangelo|last7=Haferlach|first7=Claudia|last8=Haferlach|first8=Torsten|date=2009|title=Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML|url=https://www.ncbi.nlm.nih.gov/pubmed/19587375|journal=Blood|volume=114|issue=11|pages=2220–2231|doi=10.1182/blood-2009-03-213389|issn=1528-0020|pmid=19587375}}</ref>. A more recent study found that ''NPM1''-positive/''FLT3''-ITD-negative genotype predicts favorable outcomes in AML patients younger than 65 years, but not in those older than 65 years<ref>{{Cite journal|last=Ostronoff|first=Fabiana|last2=Othus|first2=Megan|last3=Lazenby|first3=Michelle|last4=Estey|first4=Elihu|last5=Appelbaum|first5=Frederick R.|last6=Evans|first6=Anna|last7=Godwin|first7=John|last8=Gilkes|first8=Amanda|last9=Kopecky|first9=Kenneth J.|date=2015|title=Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report|url=https://www.ncbi.nlm.nih.gov/pubmed/25713434|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=33|issue=10|pages=1157–1164|doi=10.1200/JCO.2014.58.0571|issn=1527-7755|pmc=4372852|pmid=25713434}}</ref>. Besides ''FLT3''-ITD, the prognostic impact of ''NPM1'' mutations in AML can be modified by the presence of other concurrent mutations. In ''NPM1'' mutated AML, concurrent mutations have been found in ''DNMT3A'' (54%), ''NRAS'' (19%), ''TET2'' (16%) and ''PTPN11'' (15%)<ref name=":1" />. ''DNMT3A'' missense mutations predicted shorter overall survival and higher cumulative incidence of relapse when stratified by ''NPM1'' mutation status, whereas '''NRAS'' truncation mutations do not correlate with clinical outcome<ref>{{Cite journal|last=Gale|first=Rosemary E.|last2=Lamb|first2=Katarina|last3=Allen|first3=Christopher|last4=El-Sharkawi|first4=Dima|last5=Stowe|first5=Cassandra|last6=Jenkinson|first6=Sarah|last7=Tinsley|first7=Steven|last8=Dickson|first8=Glenda|last9=Burnett|first9=Alan K.|date=2015|title=Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/25964253|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=33|issue=18|pages=2072–2083|doi=10.1200/JCO.2014.59.2022|issn=1527-7755|pmid=25964253}}</ref>. ''NRAS'' codon Gly12 and Gly13 mutations predict better overall survival in AML patients with concurrent ''NPM1'' and ''DNMT3A'' mutations<ref name=":1" />.

*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>.

==Familial Forms==

Put your text here

==Other Information==

Put your text here

==Links==

[[NPM1]]

==References==
<references />

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

[[Category:Cancer Genes N]]
[[Category: Oncogenes]]
[[Category: Oncogenes N]]
[[Category:Oncogenes in AML]]
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Edited by: Fabiola Quintero-Rivera 8/3/2018

HAEM4Backup:Acute Myeloid Leukemia (AML) with Mutated NPM1 - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Xinjie Xu, PhD, FACMG __TOC__ ==Cancer Category/Type== Acute Myeloid Leukemia (AML) ==Cancer Sub-Classification / Subtype== Acute myeloid leukaemia..."

Bailey.Glen: Created page with "==Primary Author(s)*== Xinjie Xu, PhD, FACMG TOC ==Cancer Category/Type== Acute Myeloid Leukemia (AML) ==Cancer Sub-Classification / Subtype== Acute myeloid leukaemia..."