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000308899 1001_ $$aStasik, Sebastian$$b0
000308899 245__ $$aPRDM16 expression is an independent prognostic factor in AML with the double-mutant NPM1/FLT3-ITD genotype.
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000308899 520__ $$aPRDM16 (PR Domain Containing 16) is a transcription factor that plays a critical role in hematopoietic stem cell maintenance. In acute myeloid leukemia (AML), PRDM16 overexpression is linked to specific cytogenetic risk groups and poor prognosis. However, in NPM1-mutated AMLs, PRDM16 expression varies widely, with no consensus on its prognostic significance. To understand molecular and clinical associations of PRDM16 expression in this relevant subgroup, we screened 503 adult NPM1-mutant AML patients. High PRDM16 expression was associated with mutations in DNMT3A (57% vs 22%; p < 0.0001) and FLT3-ITD (51% vs 37%; p = 0.0258), and therefore a higher rate of ELN2022 intermediate-risk (42% vs 26%; p = 0.01), compared to low PRDM16 expression. Accordingly, PRDM16 overexpression was not associated with clinical outcome in multivariable analysis adjusting for ELN2022 risk in the unselected NPM1-mutant AML cohort. However, within the double-mutant NPM1/FLT3-ITD subgroup (n = 200), low PRDM16 expression was an independent prognostic factor for longer survival (hazard ratio [95%-CI] 0.467 [0.270-0.807]; p = 0.006). On a molecular level, low PRDM16 expression was associated with mutations in epigenetic regulators (TET2, IDH1/2) and increased PRDM16 promoter methylation, suggesting impaired TET/IDH-mediated DNA-demethylation as underlying mechanism. Notably, IDH1 R132C and IDH2 R140Q alterations particularly contributed to higher PRDM16 promoter methylation and reduced expression. These results suggest an association of PRDM16 overexpression with the NPM1/FLT3-ITD/DNMT3A triple-mutant AML genotype, typically linked to high leukemia stem cell frequencies and poor prognosis. Importantly, within this adverse AML subtype low PRDM16 expression is an independent prognostic marker for favorable outcome, supporting an anti-leukemic mechanism in AMLs with repressed PRDM16 transcription.
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000308899 650_7 $$2Other$$aPRDM16 expression
000308899 650_7 $$2Other$$aAcute Myeloid Leukemia (AML)
000308899 650_7 $$2Other$$aClinical Outcome
000308899 650_7 $$2Other$$aMolecular associations
000308899 650_7 $$0117896-08-9$$2NLM Chemicals$$aNucleophosmin
000308899 650_7 $$2NLM Chemicals$$aNPM1 protein, human
000308899 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$afms-Like Tyrosine Kinase 3
000308899 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aFLT3 protein, human
000308899 650_7 $$2NLM Chemicals$$aNuclear Proteins
000308899 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000308899 650_7 $$2NLM Chemicals$$aTranscription Factors
000308899 650_7 $$2NLM Chemicals$$aPRDM16 protein, human
000308899 650_7 $$0EC 2.1.1.37$$2NLM Chemicals$$aDNA Methyltransferase 3A
000308899 650_7 $$2NLM Chemicals$$aDNMT3A protein, human
000308899 650_7 $$0EC 2.1.1.37$$2NLM Chemicals$$aDNA (Cytosine-5-)-Methyltransferases
000308899 650_2 $$2MeSH$$aHumans
000308899 650_2 $$2MeSH$$aNucleophosmin
000308899 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: genetics
000308899 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: mortality
000308899 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: diagnosis
000308899 650_2 $$2MeSH$$aLeukemia, Myeloid, Acute: metabolism
000308899 650_2 $$2MeSH$$aMale
000308899 650_2 $$2MeSH$$afms-Like Tyrosine Kinase 3: genetics
000308899 650_2 $$2MeSH$$aFemale
000308899 650_2 $$2MeSH$$aMiddle Aged
000308899 650_2 $$2MeSH$$aAdult
000308899 650_2 $$2MeSH$$aNuclear Proteins: genetics
000308899 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000308899 650_2 $$2MeSH$$aDNA-Binding Proteins: biosynthesis
000308899 650_2 $$2MeSH$$aTranscription Factors: genetics
000308899 650_2 $$2MeSH$$aTranscription Factors: biosynthesis
000308899 650_2 $$2MeSH$$aAged
000308899 650_2 $$2MeSH$$aPrognosis
000308899 650_2 $$2MeSH$$aMutation
000308899 650_2 $$2MeSH$$aDNA Methyltransferase 3A
000308899 650_2 $$2MeSH$$aGene Expression Regulation, Leukemic
000308899 650_2 $$2MeSH$$aGenotype
000308899 650_2 $$2MeSH$$aAged, 80 and over
000308899 650_2 $$2MeSH$$aYoung Adult
000308899 650_2 $$2MeSH$$aDNA (Cytosine-5-)-Methyltransferases: genetics
000308899 7001_ $$aEckardt, Jan-Niklas$$b1
000308899 7001_ $$aRöllig, Christoph$$b2
000308899 7001_ $$aBaldus, Claudia D$$b3
000308899 7001_ $$aServe, Hubert$$b4
000308899 7001_ $$aMüller-Tidow, Carsten$$b5
000308899 7001_ $$aSchäfer-Eckart, Kerstin$$b6
000308899 7001_ $$aKaufmann, Martin$$b7
000308899 7001_ $$aKrause, Stefan W$$b8
000308899 7001_ $$aHänel, Mathias$$b9
000308899 7001_ $$aNeubauer, Andreas$$b10
000308899 7001_ $$aEhninger, Gerhard$$b11
000308899 7001_ $$aPlatzbecker, Uwe$$b12
000308899 7001_ $$0P:(DE-He78)2a9091646ed378ef030a77fd32aedf79$$aBornhäuser, Martin$$b13
000308899 7001_ $$aSchetelig, Johannes$$b14
000308899 7001_ $$aMiddeke, Jan M$$b15
000308899 7001_ $$aThiede, Christian$$b16
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