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WO2020111809A1 - Procédé fournissant des informations pour la prédiction du pronostic du cancer du sang après la transplantation de cellules souches hématopoïétiques - Google Patents

Procédé fournissant des informations pour la prédiction du pronostic du cancer du sang après la transplantation de cellules souches hématopoïétiques Download PDF

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WO2020111809A1
WO2020111809A1 PCT/KR2019/016556 KR2019016556W WO2020111809A1 WO 2020111809 A1 WO2020111809 A1 WO 2020111809A1 KR 2019016556 W KR2019016556 W KR 2019016556W WO 2020111809 A1 WO2020111809 A1 WO 2020111809A1
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hematopoietic stem
leukemia
stem cell
chimerism
transplantation
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Korean (ko)
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김용구
김명신
이종미
한은희
박성수
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Industry Academic Cooperation Foundation of Catholic University of Korea
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Industry Academic Cooperation Foundation of Catholic University of Korea
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer

Definitions

  • the present invention relates to a method for providing information for predicting the prognosis of blood cancer after hematopoietic stem cell transplantation.
  • Hematologic malignancies or hematologic cancers are various, but associated cancers originating from bone marrow or lymphoid tissues that affect blood function.
  • Each year, new cases of leukemia, Hodgkin's and non-Hodgkin's lymphoma and myeloma account for almost 10% of all new cancer cases diagnosed in the United States.
  • Targeted therapies using antibodies and kinase inhibitors eg, Imatinib-BCR-ABL inhibitors
  • Imatinib-BCR-ABL inhibitors have been developed, but they still rely heavily on chemotherapy and radiation therapy to treat blood cancer. They usually exhibit significant side effects and produce low efficacy.
  • MDS Myelodysplastic syndromes
  • HMA hypomethylating agents
  • HMT hypomethylating therapy
  • MDS Revised International Prognostic Scoring System
  • IVS-R Revised International Prognostic Scoring System
  • a subject is said to exhibit a minimum residual disease (MRD) if the subject has less than 5% of the hair cells in the bone marrow and indicates molecularly detectable cancer.
  • MRD minimum residual disease
  • Complete molecular relaxation is achieved when no MRD is detected ( ⁇ 10 -4 , ie less than one leukemia cell per 10 4 bone marrow cells is detectable).
  • MRD is an independent prognostic factor in adult acute lymphocytic leukemia, as already revealed in pediatric leukemia (Bruggemann et al. Blood 107 (2006), 1116-1123; Raff et al. Blood 109 (2007), 910-915).
  • hematopoietic stem cell transplantation a treatment that removes cancer cells and their own hematopoietic stem cells and then transplants new hematopoietic stem cells with powerful anti-cancer chemotherapy alone or radiation therapy in patients with hematologic cancer, has previously Transplanting by utilizing all types of hematopoietic stem cells present in peripheral blood (PB) and cord blood (CB) beyond the scope of bone marrow transplantation (BMT) Speak.
  • PB peripheral blood
  • CB cord blood
  • BMT bone marrow transplantation
  • Allogeneic hematopoietic stem cell donors may have different sex and blood types from patients, but all or part of the human leukocyte antigen (HLA) type must be correct, and bone marrow suppression due to pretreatment therapy After a period of time, until the hematopoietic stem cells of other people settle in the bone marrow of the patient and create new blood cells (called engraftment), keep in mind the side effects of infection and maintain conservative treatment.
  • HLA human leukocyte antigen
  • bone marrow or erythrocyte phenotyping tests have low sensitivity and predict changes in clinical features early. There are difficult disadvantages. Cytogenetic testing is difficult to obtain useful information in the case of a normal karyotype with no specific chromosomal abnormality at the time of diagnosis, or in the case of hematopoietic stem cell transplantation of the same sex. In addition, the molecular genetics test also has a high sensitivity, but there has been a problem that cannot be used as an indicator of follow-up when there is no specific rearrangement at the time of diagnosis.
  • hematopoietic stem cell transplantation is mainly performed in a blood-related relationship, there are many cases in which alleles are similar, so it is necessary to simultaneously perform tests on multiple markers to select useful markers for information provision.
  • the chimerism test which compares donor-patient genetic polymorphism changes, can be a useful indicator for follow-up because it can determine the current state of hematopoietic cells.
  • Mixed chimerism refers to a state in which the bone marrow cells of a patient after hematopoietic stem cell transplantation are not completely replaced by the bone marrow cells of the donor, but the donor and the patient's cells are present together.
  • Complete chimerism refers to a state in which the patient's bone marrow is composed entirely of donor cells, and a successful transplant aims to become a complete chimerism state.
  • An object of the present invention is to develop a method for providing information for predicting the prognosis of blood cancer after hematopoietic stem cell transplantation.
  • the present invention provides an NGS panel for prognostic diagnosis of hematologic cancer after hematopoietic stem cell transplantation.
  • the present invention provides a composition for diagnosing blood cancer prognosis after hematopoietic stem cell transplantation.
  • the present invention provides a kit for diagnosing blood cancer prognosis after hematopoietic stem cell transplantation.
  • the present invention provides a method for analyzing micro residual disease and chimerism after NGS-based hematopoietic stem cell transplantation.
  • the present invention provides a method for providing information for predicting the prognosis of blood cancer after hematopoietic stem cell transplantation.
  • the NGS panel of the present invention can accurately and rapidly analyze the microscopic residual disease (MRD) of the hematopoietic stem cell transplanted individual and the chimerism of the hematopoietic stem cell transplanted and donor individual, so as to accurately and rapidly leukemia. And it can predict the prognosis of blood cancer, including lymphoma, etc., it can be usefully used in related industries.
  • MRD microscopic residual disease
  • FIG. 1 is a diagram schematically illustrating a disease-related gene mutation analysis algorithm for evaluating microscopic residual disease.
  • FIG. 2 is a diagram showing a next-generation base sequencing panel for screening mutations in genes associated with diagnosis and prognosis of blood tumor diseases for evaluating microscopic residual disease.
  • FIG. 3 is a diagram showing a next-generation base sequencing panel for selecting mutations of specific genes associated with diagnosis and prognosis of blood tumor disease for evaluating microscopic residual disease.
  • FIG. 4 is a diagram showing a next-generation base sequencing panel for selecting mutations of specific genes associated with diagnosis and prognosis of blood tumor disease for the evaluation of microscopic residual disease.
  • FIG. 5 is a diagram schematically showing a chimerism analysis algorithm using SNP for NGS analysis for chimerism analysis.
  • KRGDB Korean Genome Database
  • FIG. 7 is a diagram showing the chromosome (chromosome, chr), coordinate, DB SNP ID, KRGDB information of SNP selected as useful for chimerism analysis.
  • FIG. 8 is a diagram showing the read depth, %BE and %ME of selected SNPs selected for NGS chimerism analysis.
  • FIG. 9 is a diagram showing the results of analysis of disease-related gene mutations using the developed algorithm of the present invention.
  • FIG. 10 is a view showing the results of evaluating microscopic residual disease through quantitative analysis of disease-related mutations after hematopoietic stem cell transplantation.
  • f Integrated genome viewer of SETBP1 region before/after HSCT of patient 1.
  • 13 is a diagram showing fully donor chimerism with 0.03 ⁇ 0.05% mutant allele burden for 9 patients (1-9).
  • FIG. 14 is a diagram showing the results of analysis using the chimeric analysis algorithm of the present invention.
  • terminal are terms used to properly represent a preferred embodiment of the present invention, which may vary according to a user, an operator's intention, or customs in the field to which the present invention pertains. Therefore, definitions of these terms should be made based on the contents throughout the specification. Throughout the specification, when a part “includes” a certain component, it means that the component may further include other components, not to exclude other components, unless otherwise stated.
  • the present invention ABCA12, ABL1, ASXL1, ATM, ATRX, ATXN7L1, BCOR, BRAF, BRCC3, CALR, CBL, CBLB, CD101, CEBPA, CREBBP, CSF1R, CSF3R, CTCF, CUX1, DNMT1, DNMT3A, EGFR , EP300, ERG, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HIPK2, IDH1, IDH2, INVS, IRF1, JAK2, KDM2B, KDM6A, KIT, KMT2A, KMT2D, KRAS, LAMB4, MECOM3, MELL, MET , MLL5, MN1, MPL, NCOR2, NF1, NLRP1, NOTCH1, NPM1, NRAS, NRD1, NUP98, OCA2, PDGFRA, PHF12, PHF6, PRPF40B, PRPF8, PTPN11, RAD21, RAD50
  • the NGS panel of the present invention can simultaneously analyze Micro Residual Disease (MRD) and chimerism.
  • MRD Micro Residual Disease
  • the most useful locus for chimeric analysis may be rs1523721 at position 215928972 of ABCA12 gene chromosome 2.
  • the NGS panel of the present invention may include location information for target regions for specifically detecting the genes.
  • probes specific to the region shown in FIG. 4 of the genes may be included.
  • it may be a NGS panel for NGS analysis method using a target capture method.
  • the blood cancer is chronic osteomyelocytic leukemia (CMMoL), Waldenstrom macroglobulinemia, Hodgkin's disease (HD), non-Hodgkin's lymphoma (NHL), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophil leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large cell lymphoma (ALCL) , Prelymphocytic leukemia (PML), juvenile bone marrow constitutive leukemia (JMML), adult T-cell ALL, AML with trilineal bone marrow dysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS) ), myeloproliferative disorder (MPD) and multiple myelo
  • NGS Next-generation sequencing, next-generation sequencing
  • Massive parallel sequencing large-scale sequencing, or large-scale parallel sequencing. It refers to an analysis method that rapidly deciphers a large amount of genomic information by decomposing one genome into countless pieces, reading each piece simultaneously, and combining the obtained data using bioinformatics techniques. Unlike the conventional Sanger method, it is possible to produce a large amount of parallel data, and it is an analysis method that reads the base through a process of image processing by amplifying the DNA sequence and then photographing a fluorescent marker with a camera.
  • the analysis equipment of the next-generation sequencing various platforms have been released according to unique characteristics and advantages and disadvantages according to detailed technologies such as the chemical reaction and the sequence detection principle used.
  • Diagnosis in the present invention is to determine the susceptibility of an object to a specific disease or condition, to determine whether an object currently has a specific disease or condition, as long as the disease or condition Determining an object's prognosis (e.g., identification of a pre-metastatic or metastatic cancer state, determining the stage of the cancer or determining the responsiveness of the cancer to treatment), or terrametrics (e.g., for therapeutic efficacy) And monitoring the state of the object to provide information).
  • prognosis e.g., identification of a pre-metastatic or metastatic cancer state, determining the stage of the cancer or determining the responsiveness of the cancer to treatment
  • terrametrics e.g., for therapeutic efficacy
  • prognosis refers to a prospect for future symptoms or progress determined by diagnosing a disease.
  • the prognosis usually refers to the recurrence of cancer or the metastasis or survival within a certain period after surgical procedure.
  • Prognosis prediction is a very important clinical task, as it provides clues on the direction of cancer treatment in the future, including chemotherapy in early cancer patients. Prognosis predictions also include patient response to disease treatments and predictions of treatment progress.
  • the term "probe” means a nucleic acid fragment such as RNA or DNA corresponding to a few bases to a few hundred bases, which can achieve specific binding with DNA, and is labeled to confirm the presence or absence of a specific mRNA.
  • the probe may be manufactured in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, or an RNA probe.
  • NGS can be performed by a target capture method using an RNA probe complementary to a specific region of the gene of FIG. 4. Suitable probe selection and hybridization conditions can be modified based on those known in the art, and the present invention is not particularly limited.
  • amplification refers to a reaction that amplifies a nucleic acid molecule.
  • Various amplification reactions have been reported in the art, which are polymerase chain reactions (hereinafter referred to as PCR) (US Pat. Nos. 4,683,195, 4,683,202, and 4,800,159), reverse transcriptase-polymerase chain reactions (hereinafter referred to as RT-PCR) (Sambrook et al., Molecular Cloning.A Laboratory Manual, 3rd ed.Cold Spring Harbor Press (2001)), Miller, HI (WO 89/06700) and Davey, C. et al.
  • PCR polymerase chain reactions
  • RT-PCR reverse transcriptase-polymerase chain reactions
  • NASBA nucleic acid sequence based amplification
  • LAMP strand disp amplification lacement amplification and loop-mediated isothermal amplification
  • the present invention relates to a composition for diagnosing blood cancer prognosis after hematopoietic stem cell transplantation comprising the NGS panel of the present invention and a kit for diagnosing blood cancer prognosis after transplantation of hematopoietic stem cells comprising the same.
  • the present invention provides (1) separating DNA from a sample isolated from a subject; (2) ABCA12, ABL1, ASXL1, ATM, ATRX, ATXN7L1, BCOR, BRAF, BRCC3, CALR, CBL, CBLB, CD101, CEBPA, CREBBP, CSF1R, CSF3R, CTCF, CUX1, DNMT1 , DNMT3A, EGFR, EP300, ERG, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HIPK2, IDH1, IDH2, INVS, IRF1, JAK2, KDM2B, KDM6A, KIT, KMT2A, KMT2D, KRAS , MET, MLL3, MLL5, MN1, MPL, NCOR2, NF1, NLRP1, NOTCH1, NPM1, NRAS, NRD1, NUP98, OCA2, PDGFRA, PHF12, PHF6, PRPF40B, PRPF8,
  • the sample may be any one or more selected from tissue, cells, whole blood, serum, plasma, semen, vaginal cells, hair, saliva, sputum, cerebrospinal fluid, bone marrow and urine, and is more preferably peripheral blood or bone marrow. desirable.
  • the present invention provides (1) DNA separation from a sample isolated from a hematopoietic stem cell transplanted subject; (2) ABCA12, ABL1, ASXL1, ATM, ATRX, ATXN7L1, BCOR, BRAF, BRCC3, CALR, CBL, CBLB, CD101, CEBPA, CREBBP, CSF1R, CSF3R, CTCF, CUX1, DNMT1, DNMT3A, EGFR, EP300, ERG , ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HIPK2, IDH1, IDH2, INVS, IRF1, JAK2, KDM2B, KDM6A, KIT, KMT2A, KMT2D, KRAS, LAMB4, MECOM, MET, MLLN, MLLN, , MPL, NCOR2, NF1, NLRP1, NOTCH1, NPM1, NRAS, NRD1, NUP98, OCA2, PDGFRA,
  • the gene and SNP analysis are next-generation sequencing (NGS), Sanger sequencing, and single-molecule real-time sequencing. ), Ion semiconductor analysis, Pyrosequencing, SBS (Sequencing by synthesis), SBL (Sequencing by ligation) and one or more methods selected from the group consisting of chain termination can be used. It is more preferable to analyze by the next-generation sequencing method using the NGS panel of the present invention.
  • chimeric analysis shows that when the SNP before transplantation is homozygous (aa) and after transplantation to heterozygous (Aa), the wild type base refers to the base originating from the donor cell. Was confirmed. On the other hand, when the SNP before transplantation was heterozygous (Aa) and changed to homozygous (aa) after transplantation, the substituted base would have originated in the donor or patient's cells and was detected (even if the percentage was low). ) The wild type base was confirmed to mean the base originating from the patient's remaining cells.
  • single nucleotide polymorphism in the present invention is polymorphism in a single nucleotide. That is, there is a case where one base in the entire genome of a population is different for each chromosome in a certain group. Typically, at least 3 million are present in the entire human genome DNA because SNPs are present in about 300 to 1000 bases. SNP is present.
  • next-generation sequencing panel was constructed containing genes that are frequently mutated in patients with MDS and myeloproliferative neoplasia. Specifically, 87 ABCA12, ABL1, ASXL1, ATM, ATRX, ATXN7L1, BCOR, BRAF, BRCC3, CALR, CBL, CBLB, CD101, CEBPA, CREBBP, associated with MDS and myeloproliferative tumor formation according to the algorithm of FIG.
  • Homozygous and heterozygous alleles were determined by base frequency of 90 to 100% and 45 to 60%, respectively, and 153 SNPs with heterozygous frequencies of 0.2 to 0.8 in the Korean database (Fig. 7) were examined and NGS key SNPs that were optimal for the analysis of the merism were selected according to the following criteria: 1)> 500 mean read depth; 2) ⁇ 0.2% background error (BE); And 3) ⁇ 10% measurement error of heterozygous allele (ME, difference in readings between reference and alternative alleles).
  • STR analysis was performed using AmpFlSTR Identifier PCR Amplification (Applied Biosystems, Warrington, UK) using 16 conventional markers (D8S1179 of chromosome 8, D21S11 of 21q11.2-q21, D7S820 of 7q11.2-22, D7S820, 5q33.3-34 CSF1PO, 3p D3S1358, 11p15.5 TH01, 13q22-31 D13S317, 16q24-qter D16S539, 2q35-37.1 D2S1338, 19q12-13.1 D19S433, 12p12-pter vWA, 2p23-2per TPOX, 18q21 .3 D18S51, 5q21-31 D5S818, 4q28 FGA, and X (p22.1-22.3) and Y (p11.2) chromosome amelogenin loci).
  • NGS analysis is a next-generation base sequence containing 87 genes (FIGS. 2 and 3) that are frequently mutated in patients with MDS and myeloproliferative neoplasia selected according to the algorithm of FIG. 1 in the above example. This was done using the analysis panel.
  • Target capture sequencing was performed using a custom target kit (3039061, Agilent Technologies, Santa Clara, CA, USA). DNA library was performed using the SureSelct Target Enrichment System Kit (G7530-90000) (Agilent, CA). Was produced.
  • Covaris S2 (Covaris, MA) instrument
  • 500 ng genomic DNA per sample is sheared into pieces of about 250 bp and hybridized to a target-specific capture library (Bait ID: 3039061).
  • the amount of the prepared library was quantified using KAPA Library Quantification Kit (KK4824, Kapa Biosystems), and the quality and size distribution of the adapter-coupled library were measured using electrophoresis on Agilent Bioanalyzer High Sensitivity DNA microfluidic chips (Agilent, CA).
  • the library was sequenced with Illumina HiSeq2500, cluster generation was performed in the instrument, and image analysis was performed using HiSeq control Software version 1.8.4.
  • cutadapt https://doi.org/10.14806/ej.17.1.200
  • sickle https://github.com/najoshi/sickle
  • the Burrows-Wheeler aligner https://doi.org/10.1093/bioinformatics/btp324
  • GATK Genome Analysis ToolKit
  • the pre-allo-HSCT and post-allo-HSCT mutations for ASXL1 and EZH2 mutations were performed in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT).
  • allo-HSCT allogeneic hematopoietic stem cell transplantation
  • microscopic residual disease was evaluated through quantitative analysis of disease-related mutations after hematopoietic stem cell transplantation (FIG. 9).
  • ASXL1 and EZH2 mutations exist in patients before hematopoietic stem cell transplantation, but that ASXL1 and EZH2 mutations are low in patients after hematopoietic stem cell transplantation (FIG. 10 ).
  • NGS analysis was performed as in the above example, and the donor allele burden of each SNP was calculated by the following equations 1-4.
  • Donor chimerism was defined as the average donor allele burden.
  • Patient 13 showed mixed chimerism until 7 months after allo-HSCT, and NRAS mutation was observed at diagnosis but disappeared after allo-HSCT.
  • the patient relapsed with AML at 9 months after allo-HSCT with reduced donor chimerism.
  • new cytogenetic abnormalities were obtained without recurrence of the NRAS mutation (FIG. 11E ).
  • patient 14 confirmed the effectiveness of the analysis algorithm.
  • IRA useful recipient alleles
  • the wild type base refers to a base originating from a donor cell
  • SNP before transplantation When it is heterozygous (Aa) and changed to homozygous (aa) after transplantation, the substituted base would have originated in the donor or patient's cells, and the detected wild type base (even if the percentage is low) is the patient It was confirmed that it means the base originated from the remaining cells of. Through this, it was confirmed that allele frequency data can be used for chimeric analysis by comparing before and after transplantation.

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Abstract

Procédé fournissant des informations pour la prédiction du pronostic du cancer du sang après la transplantation de cellules souches hématopoïétiques. La présente invention fournit un panel NGS pouvant simultanément analyser la maladie résiduelle minimale (MRM) d'individus transplantés avec des cellules souches hématopoïétiques, et le chimérisme d'individus transplantés avec des cellules souches hématopoïétiques et des individus donneurs, et peut prédire avec précision et rapidement le pronostic de cancers du sang, y compris la leucémie et le lymphome, et peut donc être utile dans les industries connexes.
PCT/KR2019/016556 2018-11-29 2019-11-28 Procédé fournissant des informations pour la prédiction du pronostic du cancer du sang après la transplantation de cellules souches hématopoïétiques Ceased WO2020111809A1 (fr)

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KR1020190117369A KR102236717B1 (ko) 2018-11-29 2019-09-24 조혈모세포 이식 후 혈액암 예후 예측을 위한 정보 제공 방법

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018162696A1 (fr) * 2017-03-10 2018-09-13 Institut Pasteur Variations génétiques communes au niveau du locus tcra-tcrd associé à la régulation de la fonction thymique chez les êtres humains
CN108707670A (zh) * 2018-06-11 2018-10-26 北京大学人民医院 一种在b-all患者中有预后评估意义的标记物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018162696A1 (fr) * 2017-03-10 2018-09-13 Institut Pasteur Variations génétiques communes au niveau du locus tcra-tcrd associé à la régulation de la fonction thymique chez les êtres humains
CN108707670A (zh) * 2018-06-11 2018-10-26 北京大学人民医院 一种在b-all患者中有预后评估意义的标记物

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Title
CHOI, H. W. ET A.: "Alteration of the SETBP1 gene and splicing pathway genes SF3B1, U2AF1, and SRSF2 in childhood acute myeloid leukemia", ANNALS OF LABORATORY MEDICINE, vol. 35, 2015, pages 118 - 122, XP055713194 *
EL-SHARKAWI, D.: "ASXL1 mutations are infrequent in young patients with primary acute myeloid leukemia and their detection has a limited role in therapeutic risk stratification", LEUKEMIA & LYMPHOMA, vol. 55, no. 6, 2014, pages 1326 - 1331 *
GAM, R. ET AL.: "Genetic association of hematopoietic stem cell transplantation outcome beyond histocompatibility genes", FRONTIERS IN IMMUNOLOGY, vol. 8, 8 April 2017 (2017-04-08), pages 380, XP055713218 *
KARAESMEN, E.: "Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant", BLOOD, vol. 130, no. 13, 28 September 2017 (2017-09-28), pages 1585 - 1596, XP055713214 *
KIM, J.: "SNP-based next-generation sequencing reveals low-level mixed chimerism after allogeneic hematopoietic stem cell transplantation", ANNALS OF HEMATOLOGY, vol. 97, no. 9, 12 April 2018 (2018-04-12), pages 1731 - 1734, XP036562499, DOI: 10.1007/s00277-018-3325-6 *
KIM, T. H.: "Next-generation sequencing-based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse", BLOOD, vol. 132, no. 15, 11 October 2018 (2018-10-11), pages 1604 - 1613, XP055713200 *
LEVIS, M. J.: "A next-generation sequencing-based assay for minimal residual disease assessment in AML patients with FLT3-ITD mutations", BLOOD ADVANCES, vol. 2, no. 8, 24 April 2018 (2018-04-24), pages 825 - 831 *

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