Juan Ma 1, Jennifer Dunlap 2, Lisong Shen 1, Guang Fan 2 1
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1 Juan Ma 1, Jennifer Dunlap 2, Lisong Shen 1, Guang Fan 2 1 Xin Hua Hospital, Shanghai, China 2 Oregon Health & Science University, Portland, OR, United States
2 AML is a hematopoietic neoplasms characterized by clonal expansion of myeloid blast in peripheral blood (PB), bone marrow(bm) or other tissue. Heterogeneous disease with cytogenetic aberrations, recurrent somatic mutations. Blast (myeloblasts and/or monoblasts/promonocytes and/or megakaryoblasts) percentage 20%
3 AML with recurrent genetic abnormality (regardless of blast count) AML with t(8;21)(q22;q22) AML with inv(16)(p13.1;q22) or t(16,16)(p13.1;q22) Acute promyelocytic leukemia with t(15;17)(q22;q12) AML with t(9;11)(p22;q23) AML with other recurrent genetic abnormality AML with myelodysplasia-related changes AML, not otherwise specified(nos) AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia (AMML) Acute monocytic leukemia (AMoL) Acute erythroid Leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Therapy-related myeloid neoplasms Others
4 AMML and AMoL We report mutations in AMML and AMoL using targeted Next generation sequencing(ngs). Clinical feature: Extramedullary involvement (cutaneous, central nervous system.et) Acute Myelomonocytic Leukemia (AMML): 1. Blast(myeloblasts + monoblasts + promonocytes) 20%; 2. Neutrophil and their precursors 20%; 3. Monocytes and their precursors 20%. Acute Monocytic Leukemia (AMoL): 1. Monocytic lineage (monoblasts + promonocytes + monocytes) 80%; 2. monoblasts + promonocytes 80%.
5 Morphology Immunophenotype Flow cytometry Cytogenetics Karyotypes FISH Molecular Test Single mutation test PCR Multiple mutation test NGS Panel
6 Flow cytometry Blast marker: CD34 CD117 Myeloid marker:cd13 CD33 Monocytic marker:cd14 CD64 Special Stains MPO(Myeloperoxidase) BE(Butyrate esterase)
7 AP Im, AR Sehgal, MP Carroll. et al. Leukemia September ; 28(9):
8 AP Im, AR Sehgal, MP Carroll. et al. Leukemia September ; 28(9):
9 Targeted-NGS-Panel (42 genes) designed by OHSU which used by this study Class I Class II Epigenetic -pathway Kinase Signalingmolecules/others Transcriptionalfactor Tumor suppressor /others DNA Methylation Histone Modifier Spliceosome FLT3, KIT,JAK1, JAK2, JAK3, ABL1 PTPN11,NRAS, KRAS, HRAS, CSF3R, MPL, IL7R,CBL, CBLB, NOTCH1 NPM1, RUNX1, CEBPA, GATA1, GATA2,PAX5,CREBBP,ETV6, IKZF1,STAT3 TP53, WT1, FBXW7 DNMT3A, IDH1, IDH2,TET2 ASXL1, SUZ12, EZH2, KDM6A/UTX, BCOR SF3B1, SRSF2, U2AF1, ZRSR2
10 NGS NGS can simultaneously detect multiple mutations in one sample. Massively parallel sequencing Whole genome sequencing Whole exome sequencing Targeted gene sequencing (Genes of interest/mutation hotspots) Slides from Jennifer Dunlap, OHSU
11 Average# of DNA sequence reads (depth of coverage) for each genes: 1000 The minimum detectable mutant allele frequency 5%. Percent of gene covered by a minimum of 100 sequence reads.
12 Epigenetic-Pathway Genes Grant E. Nybakken, Adam Bagg. The Genetic Basis and Expanding Role of Molecular Analysis in the Diagnosis, Prognosis, and Therapeutic Design for Myelodysplastic Syndromes. The Journal of Molecular Diagnostics, Volume 16, Issue 2, 2014, Slides from Guang Fan, OHSU
13 Patients 34 AMML, 16 AMoL Pathology department/knight diagnostic laboratory Oregon Health & Science University (OHSU) ( ). Method Sample: 20ng of DNA from patients using Ion-Torrent-PGM. Targeted-NGS-panel:42 genes relevant to hematopoietic malignancies Bioinformatics-analysis was performed by Torrent-Suite-v.3.2 -pipeline (Life-Technologies, CA).
14
15 1. Mutations in epigenetic-pathway were common in AMML/AMoL All cases: 54% (27/50) Cytogenetically-normal (CN) cases 100% (19/19) Abnormal-cytogenetic cases 26% (8/31) 2. DNMT3A mutation DNMT3 was the most frequently mutated gene in epigenetic-pathway (13/27, 48%). DNMT3A occurred with FLT3-ITD (7/13, 54%),NPM1 (11/13, 85 %) mutations. DNMT3A was mutually exclusive with MLL rearrangement. DNA Methylation (DNMT3A, IDH1/IDH2,TET2) Epigenetics-Pathway Histone Modifier (ASXL1,EZH2,et) Spliceosome (SF3B1,SRSF2,U2AF1,ZRSR2)
16 3. A patient BM with DNMT3A mutation persist in different stages Date Progress Cytogenetic Blast FLT3-ITD NPM1 DNMT3A Day-0 Initial-Diagnosis Normal 80% FLT3-ITD/(40%) p.w288fs*12/(40%) p.v636m/(94%) Day-28 End-of-induction Normal 3% undetectable undetectable p.v636m/(20%) Day-92 Relapse Normal 30% FLT3-ITD/(15%) p.w288fs*12/(10%) p.v636m/(40%)
17 The findings Correlate with our result: DNMT3A occurred with FLT3-ITD and/or NPM1 mutations were detected at high allele frequencies in AMML/AMoL!
18 Epigenetic-pathway genes in AML NGS is a powerful tool in AML
19 Mutations in epigenetic-pathway genes are common in AMML/AMoL. DNMT3A mutations always coexist with FLT3-ITD and/or NPM1, especially in the CN group. It may occurs early in tumorigenesis and may cause genetic instability which are prone to FLT3, NPM1 mutations.
20 NGS : multiple-mutation-analysis in the clinical management of AML. 1. Risk stratification Provide important markers in Diagnosis & Prognosis, particularly in CN cases. 2. Monitor disease response/relapse Minimal residual disease (MRD) DNMT3A as marker MRD and Early relapse. 3. Guide therapy Identify abnormal gene or pathway that are potential targets for therapy. Induction 3+7 [Daunorubicin or Idarubicin + Cytarabine (ara-c)] Small-molecule tyrosine kinase inhibitors (FLT3 inhibitor) Target pre-leukaemic HSCs? (DNMT inhibitors : 5-Aza-CR/5-Aza-CdR)
21 Guang Fan. MD, PhD (OHSU, OR, United States) Jennifer Dunlap. MD, PhD (OHSU, OR, United States) Lisong Shen. MD, PhD (Xin Hua Hospital, Shanghai, China) Hematopathology Department, Oregon Health & Science University(OHSU), OR, United States.
22 Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8: Welch JS, Ley TJ, et al. The Origin and Evolution of Mutations in Acute Myeloid Leukemia. Cell. 2012;150: Ding L, Ley TJ, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole genome sequencing. Nature. 2012; 481: S Wakita, H Yamaguchi.et al.mutations of the epigenetics-modifying gene (DNMT3a, TET2,IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia. Leukemia (2013) 27, Ley TJ, Ding L, Walter MJ, et al. DNMT3a mutations in acute myeloid leukemia. N Engl J Med 2010; 363: Weisberg E, Sattler M, Ray A, Griffin JD. Drug resistance in mutant FLT3-positive AML. Oncogene 2010; 29: Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 2010; 116: Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368: Schoofs T, Berdel WE, Muller-Tidow C. Origins of aberrant DNA methylation in acute myeloid leukemia. Leukemia. 2013; 28:1 14. Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood. 2013; 121: Hajkova H, Markova J, Haskovec C, et al. Decreased DNA methylation in acute myeloid leukemia patients with DNMT3A mutations and prognostic implications of DNA methylation. Leuk Res. 2012; 36: Kim, S. J. et al. A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood 2013;122, Perugini M, Iarossi DG, Kok CH, et al. GADD45A methylation predicts poor overall survival in acute myeloid leukemia and is associated with IDH1/2 and DNMT3A mutations. Leukemia. 2013; 27: Challen, G. A. et al. Dnmt3a is essential for hematopoietic stemcell differentiation. Nature Genet. 44, (2012). Shlush LI, Zandi S, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia Feb 20;506(7488): David A. RG, David H. S,et al. The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits WT DNMT3A by Blocking its Ability to Form Active Tetramers. Cancer Cell April 14; 25(4): Helin K,Dhanak D. Chromatin proteins and modifications as drug targets.nature 2013 Oct 24;502(7472):
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