Aneuploidy in Leukemia and Cancer. Claudia Haferlach MLL Munich Leukemia Laboratory

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1 Aneuploidy in Leukemia and Cancer Claudia Haferlach MLL Munich Leukemia Laboratory

2 Cancer is a genetic disease Activation of oncogenes Inactivation of tumorsuppressor genes Formation of tumorspecific fusion genes t(8;14)(q24;q32) -> CMYC overexpression amplification of MLL 17p deletion + mutation of the 2nd TP53 allele t(15;17)(q22;q12) -> PML-RARA uncontrolled proliferation blocked differentiation apoptosis resistance Cancer

3 Definition Aneuploidy loss and/or gain of whole chromosomes Trisomy 8 Monosomy 7 Aneuploidy is found in most solid tumors and half of all leukemias and lymphomas (

4 How does aneuploidy occur? Thompson S. et al. Chromosome Res 2011

5 Many players protect against aneuploidy Holland A et al., Nat Rev Mol Cell Biol 2011

6 Pathways to the generation of aneuploidy Holland A et al., Nat Rev Mol Cell Biol 2011

7 Gain of chromosomal material 46,XX 47,XX,+8

8 ALL with high hyperdiploidy

9 ALL with low hypodiploidy

10 ALL with near triploidy

11 Moorman A et al., Blood 2007

12 Number of unbalanced aberrations 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% MLL data

13 Number of unbalanced aberrations 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% ALL (n=241) ALL MLL data

14 Number of unbalanced aberrations 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% ALL (n=241) ALL CLL CLL (n=3046) MLL data

15 Number of unbalanced aberrations 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% ALL (n=241) CLL CLL ALL (n=3046) AML AML (n=2880) MLL data

16 Number of unbalanced aberrations 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% ALL (n=241) CLL CLL ALL (n=3046) AML MDS AML (n=2880) MDS (n=3487) MLL data

17 Number of imbalances per tumor Höglund M et al., GCC 2001

18 LOH on chromosome 5 and corresponding gene expression in a case with 5q deletion

19 Gene dosage effect on gene expression in AML with +8, +11, +13, -7, and del(5)(q13q31) sole vs. AML with normal karyotype Ratio 1,8 1,6 1,4 1,2 1 0,8 0,6 0,4 0,2 Chr. 8 AML +8 vs. AML-NK Chr. 11 AML +11 vs. AML-NK Chr. 13 AML +13 vs. AML-NK Chr. 7 AML -7 vs. AML-NK Chr. 5q13q31 AML del(5)(q13q31) vs. AML-NK Schoch C et al., Leukemia 2005

20 Effect of aneuploidy in combination with molecular mutations Mutation of JAK2 Chromosomes 9

21 Effect of aneuploidy in combination with molecular mutations X Mutation of TP53 Chromosomes 17 Complete loss of TP53 function

22 Different types of chromosome aberrations Albertson DG et al., Nat Genet 2003

23 Chromosome aberrations Aneuploidy/numerical aberrations Gains of whole chromosomes: Trisomy Tetrasomy Loss of whole chromosomes: Monosomy Structural aberrations Balanced aberrations: translocation inversion insertion Unbalanced aberrations: deletion, duplication, ring chromosome, translocation

24 Balanced translocation 46,XX 46,XX,t(8;21)(q22;q22)

25 Balanced rearrangements DNA mrna AAAA AAAA Protein Overexpression of a normal protein Expression of a chimeric protein t(8;14)(q24;q32) ->CMYC t(15;17)(q22;q12) -> PML-RARA inv(3)(q21q26) -> EVI1 inv(16)(p13q22) -> CBFB-MYH11

26 Molecular aberrations base exchanges: JAK2, FLT3-TKD insertions: FLT3-ITD, NPM1 deletions: IKZF1 duplications: MLL-PTD

27 Molecular aberrations base exchanges: JAK2, NRAS, FLT3-TKD

28 Molecular aberrations insertions: FLT3-ITD, NPM1 SP TM JM TK1 KI TK2 RNA JM TM TK1 exon 11 exon F M -C R 11 R - - DNA exon M -350 bp WT -cabl

29 Molecular aberrations deletions: IKZF1, RUNX1 duplications: MLL-PTD, RUNX1

30 CML Chromosome aberrations Balanced rearrangements: unbalanced aberrations: t(9;22)(q34;q11) +8 +der(22)t(9;22) i(17)(q10) t(3;21)(q26;q22) inv(3)(q21q26) Molecular aberrations base exchanges: KRAS, NRAS deletions: IKZF1 insertions: TET2 duplications: WT1

31 Progression to BC in CML on the cytogenetic level 46,XX 46,XX,t(9;22)(q34;q11) 47,XY,+8,t(9;22)(q34;q11)

32 Progression to BC in CML on the cytogenetic level MLL data

33 Progression to BC in CML on the molecular level Grossmann V et al., Leukemia 2011

34 Summary Aneuploidy is a frequent phenomenon in leukemia Different mechanisms lead to aneuploidy Aneuploidy contributes to malignancy by deregulation of gene expression loss of tumor suppressor genes copy number increase of oncogenes

35 Munich Leukemia Laboratory Cytomorphology Torsten Haferlach Johannes Schneider Eva Ammerlahn Sandra Eckstein Katharina Hermus Stefanie Jansa Michele Kyncl Katja Macijewski Laura Urmetzer Jana Wagenbreth A.-Ch. Weichselbaumer Immunophenotyping Wolfgang Kern Frauke Bellos Sabrina Baumann Angelika Eckelt Nicole Fietzeck Elena Gouberman Franziska Krakau Rita Lapping Maja Lumpe Christiane Stangl Antonia Wagner Anja Winkler Carina Zanggl Cytogenetics/FISH Claudia Haferlach Sandra Böker Silvia Finkböck Claudia Hepperger Jinda Holzwarth Doris Kestner Isabel Liebhart Verena Patterer Sarah Volkert Juliane Brendel Anna-Maria Brucks Sabina Bursch Jennifer Eland Annika Eßer Eyleen Haubner Annette Königsbauer Ulrike Schulz Kathrin Stadler Marita Staller Susann Marschner Alida März Alexandra Mohr Nicole Mudrack Katja Niklaus Maximiliane Oppl Isabel Penzler Sandra Pöstgen Cornelia Pröger Karin Seige Franziska Schäfer Nadine Schedler Susanne Schmelz Carina Schreck Martin Schröter Melanie Zenger Kathleen Zieschang Moleculargenetics Susanne Schnittger Frank Dicker Christiane Eder Annette Fasan Sabine Jeromin Simone Weber Katharina Bayer Jessica Brust Meike Büchler x Rabea Konietschke Julia Niederreiter Carina Schrauder Elisabeth Sirch Antje Stiel Madlen Ulke Nicole Wendland Christian Wittmann NGS/Microarrays Alexander Kohlmann Vera Großmann Niroshan Nadarajah Sandra Weißmann Lucia Böck Katrin Butschalowski Organisation Tamara Alpermann Peter Baumann Dirk Bursch Elke Erhard Claudia Eßbauer Julia Hägel Katrin Ilzhöfer Franziska Janou Sandra Nawroth Franziska Prantl Tina Riedel Ulrike Riese Sandra Schulze Sabrina Weiß Wenke Worseg Quality Management Janine Elosge Stefan Harbich Franziska Pötzinger Sonja Schindela Elisa Stopp Melanie Wild Monika Trnobransky

36 Number of balanced aberrations

37 Number of balanced aberrations ALL 3 4

38 Number of balanced aberrations ALL 3 CLL 4

39 Number of balanced aberrations ALL 3 CLL AML 4

40 Number of balanced aberrations ALL 3 CLL AML MDS 4

41 Regions on chromosome 5 showing a significant lower gene expression in a case with 5q deletion

42 Unbalanced abnormalities Trisomy 8 5q deletion Monosomy 7 der(1;7)(q10;p10) -> +1q,-7q

43 Effect of aneuploidy in combination with molecular mutations Mutation of JAK2 Chromosomes 9