Dysplasie in AML en (cyto)genetische. afwijkingen: Chromosoom 3q26 afwijkingen en EVI1

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1 Dysplasie in AML en (cyto)genetische afwijkingen: Chromosoom 3q26 afwijkingen en EVI1

2 patient BM H

3 patient dag 24 kuur I H

4 patient dag 24 kuur I H

5 Het betreft een patiente uit bij presentatie Hb 6.8 WBC 5.6 thrombo 412. Diagnose WHO 2008: AML met t(3;3)(q21;q26)rpn1-evi1 behandeld in de HOVON 42: na 1e kuur geen response na 2e kuur morfologisch en immunologisch in remissie daarna allo transplantatie en na 3 weken recidief en overleden. Cytogenetica: t(3;3) en -7.

6 Acute myeloid leukemia: Molecular biology Normal AML

7 Bone marrow: Morphology Normal Leukemia

8 Normal bloodcell formation Stemcell Bone marrow Blood

9 One cell transforms: The beginning of leukemia. Bonemarrow Immature cell Blood

10 Leukemia cells in bone marrow and blood Bone marrow Blood

11 AML behaves differently in different patients patient A in 1 month patient B cured patient C Cured, but one year later

12 Why do AML patients respond differently to therapy?

13 Why do AML patients respond differently to therapy? AML is not one disease AML is a disease of the genes Different AMLs have different recurrent genetic abnormalities

14 Identification of genetic defects in AML: Improved diagnostics and prognostics More specific treatment protocols

15 Identification of genetic defects in AML: Improved diagnostics and prognostics More specific treatment protocols

16 Normal: 2 x 23 chromosomes Kern Cel DNA

17 AML is a clonal disease with frequent chromosomal abnormalities. Translocation t(8;21): an example

18 percentage living Acute myeloid leukemia Prognosis based on chromosomal abnormalities 100 inv(16) t(15;17) t(8;21) favorable /7q-, t(3;3)/inv3, t(6;9), t(9;22), complex, a.o years intermediate unfavorable

19 Chromosome analysis treatment Favorable t(8;21) Chemotherapy Intermediate poor Inv (3) Chemotherapy + Transplantation

20 Chromosome analysis treatment Good t(8;21) Chemotherapy Intermediate poor Inv (3)? Chemotherapy + Transplantation

21 Chromosome 3q26 aberrations in AML 3q26 aberrations: ~2% AML Inv 3 t(3;3)

22 Cum Survival Chromosome 3q26 aberrations in AML 3q26 aberrations: ~2% AML AML with 3q26 aberrations.8 AML intermediate risk Inv t(3;3) Event free survival, [m]

23 Chromosome 3q26 aberrations in AML 3q26 aberrations: ~2% AML Inv 3 t(3;3)

24 EVI1 is the gene that is located at the breakpoint region at Chromosome 3q26 3q26 aberrations: ~2% AML 3 3 Inv 3 Evi1 t(3;3)

25 Identification of genetic defects and analysis gene expression in AML: INTERMEZZO I

26 Two cells from the same individual and thus with the same DNA

27 23 chromosomes: ~ genes. Gene: turned on Gene: turned off DNA Normal myeloid cell Skin cell Liver cell

28 22 paar chromosomen XX of XY genen/cel

29 Een chromosoom

30 DNA

31 DNA

32 DNA

33 Genen coderen voor eiwitten genen/cel

34 Een Gen start stop DNA RNA polymerase ATG TGA AAAA RNA ribosomen M-AZ-AZ-AZ-AZ-AZ-AZ EIWIT

35 EVI1 is the gene that is located at the breakpoint region at Chromosome 3q26 3q26 aberrations: ~2% AML 3 3 Inv 3 Evi1 t(3;3)

36 The EVI1 gene is located on Chromosome 3 is switched off in normal bone marrow cells. Normal marrow EVI1 off Chromosome 3

37 The EVI1 gene located on Chromosome 3 is switched on in AML with a chromosome 3q26 break. Normal marrow Leukemia EVI1 off Chromosome 3 EVI1 on Chromosome 3: break

38 treatment Favorable t(8;21) Chemotherapy Intermediate? EVI1? Poor Inv (3) Chemotherapy = EVI1 + Transplantation

39 The EVI1 gene is turned on in ~10 % subset of AML patients without a chromosome 3 break. Normal marrow Leukemia Leukemie EVI1 off Chromosome 3 EVI1 on Chromosome 3: break EVI1 on Chromosom3

40 Treatment Favorable Intermediate EVI1 expression without 3q26 break(`~10%)? Poor +

41 Combined AML cohorts revealed prognostic impact of high EVI1 levels Overall Survival (%) Event-free Survival (%) Relapse-free Survival (%) EVI1 - n= EVI1 - n=952 EVI1 - n= EVI1 + n=148 P < EVI1 + n=148 P < EVI1 + n=79 P < Time (years) Time (years) Time (years) Achievement of CR OS EFS DFS HR, 0.54; 95%CI, ( ), P=0.002 HR, 1.17; 95%CI, ( ), P=0.18 HR,1.46; 95%CI, ( ), P= HR, 1.32 ; 95%CI, ( ),P=0.05 *Cox regression model stratified for cohorts and other prognostic AML markers, age, WBC, platelets, cytogenetic risk, type of AML and NPM1wt/FLTITDneg.

42 Overall Survival (%) Relapse-free Survival (%) EVI1 + AML cases benefit of allogeneic transplant in first CR A B Allo-TPL in 1 st CR n=28 50 Allo-TPL in 1 st CR n=28 25 No Allo-TPL in 1 st CR n=51 25 No Allo-TPL in 1 st CR n=51 P =.05 0 P = Time (years) Time (years)

43 Favorable Intermediate EVI1 expression without 3q26 break (10%) + Poor +

44 De search for other genetic abnormalities continues. Favorable Intermediate Other mutation? Poor +

45 Gene expression profiling in AML

46 23 chromosomes: ~ genes. Gene: turned on Gene: turned off DNA Leukemia A Leukemia B Leukemia C

47 Gene expression profiling of AML: Expression analysis of genes The Genetic (bar)code

48 Gen expressie profiel analyse bij AML: Expressie analyse van genen The Genetic (bar)code

49 AMLs zijn morphologisch vergelijkbaar: Een studie bij 285 patienten. AML 1 AML 2 AML 3 AML 4 AML AML 283 AML 284 AML 285

50 Gen expressie profielen bij AML: Opslaan van de genetische codes bij 285 AML patiënten AML 1 AML 2 AML 3 AML 4 AML AML 283 AML 284 AML 285

51 Gene expression profiling

52 Omniviz Pearson's correlatie coefficient analyse B A

53 Omniviz Pearson's correlatie coefficient analyse A B C A A A D E F A A A

54 Analyse en vergelijking van de gen expressie profilen bij 6 AML patiënten AML patients (random order) AML patients

55 50 AML patienten Analyse en vergelijking van de gen expressie profilen bij 50AML patiënten 50 AML patienten 285 AML patients (random order) 285 AML patients

56 285 AML patienten Analyse en vergelijking van de gen expressie profielen 285 AML patienten 285 AML patients (random order) 285 AML patients

57 Clustering van AML patiënten met zelfde gen expressie profiel 285 AML patienten 285 AML patients 285 AML patients 285 AML patienten

58 285 AML patienten kunnen worden onderverdeeld in 16 subgroepen of clusters 285 AML patienten

59 285 AML patienten kunnen worden onderverdeeld in 16 subgroepen of clusters

60 285 AML patienten kunnen worden onderverdeeld in 16 subgroepen of clusters

61 Patienten met dezelfde bekende translocaties zitten in een zelfde cluster: Zelfde gen expressie profiel Inv(16) t(15;17) t(8;21)

62 Wat betekent dit voor de andere clusters? Inv(16)????? t(15;17) t(8;21)

63 Chromosome 3q26 defects in AML cases from cluster 10: EVI1 defects EVI1 +/EVI1 -

64 Cumulative percentage AML cases from cluster 10 respond poor to treatment Event free survival t(8;21), inv 16, t(15;17) 25 Cluster 10 0 Months 0 60

65 Gene profiling of AML Identification of genetically defined AML Subgroups within genetically defined AML Novel subclasses of AML Novel insight into the biology of AML

66 Acknowledgements Erasmus MC Sanne Lugthart Marije Havermans Bob Löwenberg Claudia Erpelinck Eric Bindels Chantal Goudswaard Berna Beverloo Kirsten van Lom Antoinette van Hoven-Beijen Roel Verhaak Peter Valk University of Ulm Stefan Gröschel Richard F. Schlenk Karina Eiwen Hartmut Döhner Konstanze Döhner

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