Die klonale Hämatopoese unbestimmten Potentials umfasst somatisch erworbene Mutationen, die zu einer klonalen Expansion führen, aber nicht zwingend zu einer malignen hämatologischen Neoplasie. Sie ist somit auch im Gesunden nachweisbar.
Die standardisierte Überwachung der minimalen Resterkrankung mit molekularen Methoden mittels NGS-Technik ist ein zunehmend verbreitetes Verfahren, da sie selbst geringe Mutationen zuverlässig detektiert. Der Nachweis minimaler Resterkrankung in CR ist im Vergleich zu den MRD-negativen Patienten mit einer erhöhten Rezidivrate assoziiert (HR 5.58, P<0,001, 5-Jahres CIR 66 vs. 17%). Die minimale Resterkrankung wurde in kompletter Remission vor Transplantation gemessen und identifizierte 12 Patienten mit persistierender klonaler Hämatopoese (VAF >5%). Die CIR der 12 Patienten mit hoher VAF verhielt sich ähnlich wie die der MRD-positiven Patienten im Vergleich zu MRD-negativen Patienten (HR 5.90, 95% KI 2.35-14.81, P<0.001, 5-Jahres CIR 55% vs. 17%). DNMT3A wurde als MRD-Marker vorab ausgeschlossen, da dieser bekanntermaßen nicht prognostisch relevant ist.
Andere Gene hingegen, die in der Literatur mit CHIP beschrieben sind, erwiesen sich in unserer Studie als verlässliche MRD-Marker. NGS-MRD-Positivität sowie die Persistenz der klonalen Hämatopoese waren bei uns mit einer schlechten Prognose assoziiert, unabhängig von anderen prognostischen Risikofaktoren. Die NGS-basierte MRD-Messung bietet somit einen zuverlässigen Vorhersagewert für die Rezidivwahrscheinlichkeit und das Überleben und könnte in Zukunft helfen Entscheidungen bezüglich der Stammzelltransplantation, sowie die Vor- und Nachbehandlung der Patienten zu verbessern. Hinsichtlich der klonalen Hämatopoese wären weiter Studien mit einem größeren Patientenkollektiv sinnvoll, um den Einfluss von CHIP auf den Krankheitsverlauf der AML und seine Bedeutung im Monitoring besser zu verstehen.
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89 7. Abkürzungsverzeichnis
AML Akute myeloische Leukämie
ARTA All-trans Retinolsäure, engl. All-trans-retinoic-acid ASXL1/2 Additional Sex Combs like 1/2
BCOR BCL-6 corepressor
BCORL1 BCL-6 corepressor-like protein 1 BRAF Serin/Threonin Proteinkinase
BRC-ABL Fusionsprotein aus BRC (breakpoint cluster region) und ABL (Abelson Murine Leukemia Viral Oncogene Homolog 1)
CALR Calreticulin
CBFB Core-binding Factor-Leukämie Beta CBL E3 ubiquitin- Protein Ligase CBL CD Cluster of Differentiation
CDKN2A Zyklin abhängiger Kinase Inhibitor 2A
CEBPA CCAAT Enhancer Binding Protein alpha (C/EBPalpha)
CHIP klonale Hämatopoese unbestimmten Portenzials, engl: clonal hematopoiesis of indeterminate potential
CHOP klonalen Hämatopoese mit erheblichem onkogenen Potential, engl: clonal hematopoiesis with substantial oncogenic potential CIR kumulative Rezidivinzidenz, engl: cumulative incidence of relapse CpG-Inseln Cytosin Guanin Dinukleotidinseln
CR Komplettremission, engl. Complete remission CSF3R Kolonie stimulierender Faktor 3 Rezeptor CSNK1A1 Casein kinase 1 alpha 1
CUX 1 Cut like Homeobox 1 DDX41 DEAD-box helicase 41
DEK-NUP214 Fusionsprotein aus DEK Protein Gen und Nucleoporin 214 DLI Spenderlymphozyten-Infusion, donor leukocyte infusion DNMT3A DNA (cytosine-5-)-methyltransferase 3-like
ECOG Eastern Cooperative Oncology Group;
EFS Event-free survival ELN European LeukemiaNet EPO Erythropoietin
90 ETNK1 Ethanolamin Kinase 1
ETV6 Transkriptionsfaktor ETV6 EZH2 Enhancer of zeste homolog 2
FAB French-American-British Klassifikation der AML FLT3 Fms-like tyrosine kinase-3
FLT3-ITD Interne Tandemduplikation von FLT3 FLT3-TKD Tyrosinkinase-Domäne (TKD)
GATA 2 GATA binding protein 2 HLA Humane Leukozyten Antigen
HSZ/ HSC Hämatopoetische Stammzelle, engl. Hematopoietic stem cell IDH1/2 Isocitrat-Dehydrogenase1/2
JAK2 Janus kinase 2
KDM6A Lysine demethylase 6A
KIT v-kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog
KM Knochenmark
K-RAS v-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog MDS Myelodysplastisches Syndrom
MECOM MDS1 and EVI1 complex locus MLL Mixed Lineage Leukemia
MLL-PTD Mixed Lineage Leukemia- Partielle Tandem-Duplikation
MLLT3-KMT2A Fusionsprotein aus Mixed-Lineage Leukemia Translocated To Chromosome 3 Protein und Histone-lysine N-methyltransferase 2A
MPL Thrompopoetinrezeptor Gen
MRD Minimale Resterkrankung, engl. Minimal residual disease MYC MYC Proto-Oncogene, BHLH Transcription factor
NF1 Neurofibromin 1
NGS Next Generation Sequencing NOTCH1 Notch homolog 1 Gen
NPM1 Nucleophosmin 1
NRAS Neuroblastoma RAS Viral (v-ras) Oncogene Homolog
NRM nicht durch einen Erkrankungsrückfall bedingte Mortalität, engl:
non-relapse mortality
OS Gesamtüberleben, engl. Overall Survival
91 PB peripheres Blut, engl. Peripheral Blood
PCR Polymerase Kettenreaktion, engl. Polymerase Chain Reaction PHF-6 plant homeodomain (PHD)-like finger protein 6
PML-RARα Promyelozyten Leukämie/ Retinolsäure Rezeptor Alpha, engl.
Promyelocytic Leukemia/Retinoic Acid Receptor Alpha PPM1D Protein Phosphatase 1D
PTPN11 Tyrosine protein phosphatase non-receptor type 11
qRT-PCR Quantitative Reverse Transkriptase-Polymerasekettenreaktion RAD21 RAD21 cohesin complex component Gen
RBM15-MKL1 Fusionsprotein aus RNA Binding Motif Protein 15 und megakaryoblastic leukemia 1
RFS Rezidivfreies Überleben - engl. Relaps-free survival.
RT-PCR Real Time-PCR
RUNX1 Runt-related Transcription Factor 1
SCT Stammzelltransplantation, engl. Stem Cell Transplantation.
SETBP1 SET Binding protein 1 SF3B1 splicing factor 3b subunit 1
SMC1A Structural Maintenance Of Chromosomes 1A SMC3 Structural maintenance of chromosomes 3
SNV Einzelbasenveränderung, engl. Single Nukleotid Variant SRSF2 serine and arginine rich splicing factor 2
STAG 2 Stromal Antigen 2
t-AML therapieassoziierte akute myeloische Leukämie TCGA the Cancer Genome Atlas
TET2 Ten eleven Translocation2 TP53 Tumor Suppressor Protein 53
U2AF1 U2 Small Nuclear RNA Auxiliary Factor 1 Gen WBC Leukozytenzahl, engl. White Blood Cell (Count) WHO Weltgesundheitsorganisation
WT1 Wilms Tumor 1
ZBTB7A Zinc finger and BTB Domain Containing 7A
ZRSR2 Zinc finger CCCH-type, RNA bindung motif and serine/arginin rich