title: Acute myeloid leukemia derived from lympho-myeloid clonal hematopoiesis.
abstract: We studied acute myeloid leukemia (AML) patients with lympho-myeloid clonal hematopoiesis (LM-CH), defined by the presence of DNA methyltransferase 3A (DNMT3A) mutations in both the myeloid and lymphoid T-cell compartment. Diagnostic, complete remission (CR) and relapse samples were sequenced for 34 leukemia-related genes in 171 DNMT3A mutated adult AML patients. AML with LM-CH was found in 40 patients (23%) and was associated with clonal hematopoiesis of indeterminate potential years before AML, older age, secondary AML and more frequent MDS-type co-mutations (TET2, RUNX1 and EZH2). In 82% of AML patients with LM-CH, the preleukemic clone was refractory to chemotherapy and was the founding clone for relapse. Both LM-CH and non-LM-CH MRD-positive AML patients who achieved CR had a high risk of relapse after 10 years (75% and 75%, respectively) compared with patients without clonal hematopoiesis in CR with negative MRD (27% relapse rate). Long-term survival of patients with LM-CH was only seen after allogeneic hematopoietic stem cell transplantation (HSCT). We define AML patients with LM-CH as a distinct high-risk group of AML patients that can be identified at diagnosis through mutation analysis in T cells and should be considered for HSCT.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Thol
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Klesse
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Köhler
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Gabdoulline
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kloos
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Liebich
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wichmann
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Chaturvedi
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Fabisch
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: V I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Paschka
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Bug
authors.affiliation: Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Serve
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Göhring
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Department of Hematology-Oncology, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Department of Internal Medicine III, Krankenhaus Siloah, Hannover, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kirchner
authors.affiliation: Evangelisches Krankenhaus Essen-Werden, Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wattad
authors.affiliation: Klinikum Oldenburg, Oldenburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kraemer
authors.affiliation: Klinikum Bremen-Mitte, Bremen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Hertenstein
authors.affiliation: Department of Internal Medicine V, Klinikum Lüdenscheid, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Heil
authors.affiliation: Department of Medicine II, Oncological Center, Hubertus Wald University Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Fiedler
authors.affiliation: Department of Hematology and Oncology, Klinikum Braunschweig, Braunschweig, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Krauter
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: R F
authors.initials: RF
authors.lastname: Schlenk
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Heuser
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D002999:Clone Cells; D003131:Combined Modality Therapy; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D054503:Lymphoid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A