Nieuwe inzichten in de pathogenese van AML

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2 Nieuwe inzichten in de pathogenese van AML Moderator Gerwin Huls, UMC Groningen 1st author / speaker Joop Jansen, Radboudumc Nijmegen

3 Belangenverklaring In overeenstemming met de regels van de Inspectie van de Gezondheidszorg (IGZ) Naam: Organisatie: Joop Jansen Radboudumc Nijmegen X Ik heb geen 'potentiële' belangenverstrengeling Ik heb de volgende mogelijke belangenverstrengelingen: Type van verstrengeling / financieel belang Ontvangst van subsidie(s)/research ondersteuning: Ontvangst van honoraria of adviseursfee: Lid van een commercieel gesponsord speakersbureau : Financiële belangen in een bedrijf (aandelen of opties): Andere ondersteuning (gelieve te specificeren): Wetenschappelijke adviesraad: Naam van commercieel bedrijf nvt nvt nvt nvt nvt nvt

4 Individualized treatment based on biological markers I: Prognostic marker: risk adapted treatment : adapt the severity of treatment to the prognosis of the patient eg: -bone marrow transplantation yes or no -intensity of chemotherapy II: Predictive marker: use of targeted therapies: Adapt treatment to the (genetic) lesion(s) that underlie the pathogenesis II: Monitoring effectiveness of treatment: Molecular markers allow sensitive detection of minimal residual disease

5 % of patients with a specific mutation Recurrent mutations in AML are confined to approximately 100 diffferent genes => Can we make biological sense from this? Papaemmanuil, N Engl J Med 374:232016

6 Regulatie van celgroei tijdens normale hematopoiese Stem cells mature end cells FLT3-Ligand SCF IL2 IL4 MCSF B/T cells Monocytes macrophages GCSF IL6 IL3 GMCSF EPO TPO IL7 IL5 EPO granulocytes platelets erythrocytes bone marrow Pheripheral blood

7 Pathways involved in proliferation and differentiation control P P Cell cycle d d d G0 M G1 S G2 d Gene transcription In case of abberant regulation: p53 is activated leading to apoptotis

8 Biologische classificatie van AML Gene Frequency Prognostic impact Gene function NPM % Favorable Nuclear import, apoptosis FLT3 ITD 20-25% Unfavorable Growth factor receptor DNMT3A 20-23% Unfavorable Epigenetic transcription regulation Various MLL 10-15% Unfavorable Epigenetic transcription regulation N-RAS/K-RAS 10-15% Intermediate Signal transduction CEBPA 10-15% Favorable (bi-allelic mutations) Transcription factor CBFB-MYH11 10% Favorable Transcription factor AML1-ETO 10% Favorable Transcription factor TET2 8-13% Unfavorable Epigenetic transcription regulation IDH2 6-10% Unclear Epigenetic transcription regulation PML-RAR 5-10% Favorable Transcription factor ASXL1 5-10% Unfavorable Epigenetic transcription regulation RUNX1 5-10% Unfavorable Transcription factor FLT3-TKD 5-7% Intermediate Growth factor receptor WT1 3-10% Unclear/poor Transcription factor IDH1 3-9% Unclear Epigenetic transcription regulation PTPN11 3-5% Intermediate Signal transduction C-KIT 2-6% (high in CBF leukemia) Unfavorable in CBF leukemia Growth factor receptor CBL <2% (16% in inv16) Unclear Signal transduction

9 Biologische classificatie van gemuteerde genen I: growth factor receptors extracellular II: signal transduction molecules cytoplasm III:cell cycle nucleus IV:transcription factors VI: Epigenetic regulators V:Apoptosis VII: RNA splicing factors

10 Number of mutations Number of detected mutations detected by whole exome sequencing 12 patients: 171 mutations detected in 156 genes Median nr of mutations: 13 / patient Median nr of mutations in known, recurrent myeloid malignancy-associated (driver) mutations: 3 Median number of passenger mutations: Detected mutations per patient Patient number

11 Molecular markers can be used to measure minimal residual disease MRD monitoring comes to the clinic: e.g. HOVON-132. Impact on relapse (even in allogeneic SCT setting) Ivey et al. NEJM 2016

12 Some mutations often co-occur (eg IDH1/2 and NPM1), whereas others are mutually exclusive (eg TET2 and IDH1/2) Figueroa et al, Cancer Cell, 18::

13 Epigenetic modifications. DNA methylation Addition of methyl groups to cytosines, leading to gene repression Histone modifications A combination of different molecules can be attached to histones and serve as mark for the activity of the DNA wrapped around them

14 Methylation and de-methylation of cytosines DNA methyl transferases TET proteins Passive demethylation by cell division Transcription repression Active demethylation by oxidation and deamination followed by Base excision repair

15 Connection between TET2 and IDH: The conversion of 5-mC to 5-hmC is dependent on Fe and α-keto-glutarate TET proteins α-ketoglutarate And Fe 2+ dependent

16 Isocitrate dehydrogenases IDH1 and IDH2 catalyse conversion of isocitrate into a-ketoglutarate IDH1/2 IDH1 or 2 is mutated in 5-15% of the cases of MDS and AML

17 Mutant IDH1/2 induces 2-hydroxyglutarate which inhibits TET2 function Isocitrate α-ketoglutarate 2-hydroxyglutarate Normal IDH1/2 Mutant IDH1/2 TET proteins α-ketoglutarate and Fe 2+

18 DNA methylation is regulated by various genes Mutations of these genes occures frequently in myeloid malignancies IDH % MDS 10-15% AML IDH-2 a-ketoglutarate DNMT3A 5% MDS, 20-25% AML TET 2 20% MDS, 5-10% AML Transcription repression

19 Genetic diversity between patients: multiple different combinations Patients with a NPM1 mutation Usually also have a DNMT3A mutation OR FLT3 mutation, OR a DNMT3A mutation Depending on therapy, NPM1 mutated patients may react homogeneously (eg using effective anti NPM1 therapy), or very heterogeneously depending on co-mutated genes. Patel et al, N Eng J Med :1079

20 No full set of transforming mutations: clonal hematopoiesis of indeterminate potential (CHIP) Jaiswal, NEJM 2014

21 Symbols indicate a specific (set of) mutation(s) Clonal evolution

22 Slides with clonal evolution patterns in MDS removed : In press Nature Communications

23 Conclusies Het spectrum van mutaties dat voorkomt bij AML is grotendeels bekend De aangedane genen vallen binnen een beperkt aantal biologische klassen De functie van deze genen is meestal (deels) bekend Een aantal van deze genen kan worden getarget met specifieke middelen In een patient met MDS/leukemie komen meerdere mutaties voor Sommige mutaties komen vaak samen voor andere juist niet Lineaire evolutie kan leiden tot progressieve resistentie Vertakte evolutie kan leiden tot het bestaan van vershillende subkloons die naast elkaar bestaan, en mogelijk anders reageren op therapie Wat kunnen we hier therapeutisch mee??

24 Acknowledgements Laboratory of Hematology & Dept Hematology, Radboudumc Nijmegen, The Netherlands Leonie Kroeze Pedro da Silva Coelho Thessa Koorenhof-Scheele Louis van de Locht Aniek de Graaf Marion Massop Bert van der Reijden Theo de Witte Petra Muus Nicole Blijlevens Joop Jansen Dept Bioinformatics, Munster, Germany Martin Dugas Sarah Sandmann Department of Hematology, UMCG, Groningen, The Netherlands Gerwin Huls Edo Vellenga Gerbrig Berger Institute of Hematology and Blood Transfusion, Prague, Czech Republic Monika Beličková Jaroslav Čermák Department of Human Genetics, Radboud umc, Nijmegen, The Netherlands Marian Stevens-Kroef Department of Pathology & Tumour Biology, Kyoto university, Kyoto, Japan Seishi Ogawa Kenichi Yoshida