Myelomatose -sett fra et cellebiologisk ståsted

Transkript

1 Myelomatose -sett fra et cellebiologisk ståsted KG Jebsen Center for Myeloma Research Department of Cancer Research and Molecular Medicine - NTNU anders.sundan@ntnu.no 1

2 Multiple Myeloma ( Myelomatose ) Plasma cell malignancy, monoclonal Ig marker of disease 360 new cases in Norway each year (2010) Incurable, mean survival after diagnosis is currently approx. 5-7 years, large variation between patients Survival time increased last years due to introduction of new treatments, e.g. thalidomide, bortezomib (velcade) Malignant plasma cells found in the bone marrow Osteolytic lesions common complication 2

3 Diagnosis by Serum electrophoresis Estimating the fraction of plasma cells in bone marrow aspirate - normally 2% - myeloma >10% % plasma cells? 3

4 1. Myelomceller er plasmaceller, dvs terminalt differensierte B-celler fordi cellene har gjennomgått Ig klasseskifte cellene har Ig-gener som har gjennomgått somatisk hypermutasjon dvs. cellene har møtt et antigen i en lymfeknute plasmablaster i en lymfeknute vil i tillegg aktivt stimuleres til celledeling (hyperproliferasjon) 2. Alle myelompasienter har hatt MGUS 3. MGUS plasmaceller deler seg svært sakte, men de dør ikke.. Bone Marrow Microenvironment Normal Plasmablast MGUS Myeloma in Bone Marrow Extramedullar myeloma IgH translocations, Hyperdiploidity diagnose tid 4

5 Omtrent halvparten av pasientene har myelomceller med DNA-translokasjoner der den ene parten i translokasjonen er et immunglobulingen. Eksempel t(4;14); 5

6 Dual roles of MMSET; Histone methyl transferase (H3K36 up, H3K27 down), chromatin remodelling Repair of DNA double strand breaks (H4K20) t(4;14) leads to overexpression of truncated MMSET lacking proper regulation Chesi and Bergsagel,

7 Den andre halvparten av pasientene har celler med mer enn 2 kopier (ofte 3) av hvert kromosom (cellene er hyperdiploide) OH-2 cell line 7

8 Genetic events IgH translocations (50%) Hyperdiploidity (50%)? Normal Plasmablast MGUS time MM diagnosis 8

9 Bone Marrow Microenvironment Normal Plasmablast MGUS Myeloma in Bone Marrow Extramedullar myeloma IgH translocations, Hyperdiploidity RAS mutation MYC activation NFkB activation?? Sequencing indicate at least some 50 mutations in myeloma cells at the time of diagnosis. Each patient will have myeloma clone(s) that are unique Which mutations are important? 9

10 Classification based on oncogene addiction applying pharmacological inhibitors of intracellular signalling pathways? MYC NFkB RAS 10

11 Stromal cells Stromal and myeloma cells 11

12 DRAQ5 : highly cell permeable DNA-interactive agent, with fluorescence signature extending into the infra-red region of the spectrum. YO-PRO -1 : green-fluorescent carbocyanine nucleic acid stain identifies dying cells based on membrane permeability of dying cells. 12

13 % viable celler % viable celler Melphalan Kons (um) R R Velcade Kons (nm) R R

14 Lengre overlevelse av pasientene skyldes introduksjon av nye legemidler: - Bortezomib - Thalidomide Virker bortezomib pga hemming av generell proteindegradering eller pga Hemming av degradering av et spesifikt protein (f.eks IkB)? 14

15 Celler kan degradere eget protein på to måter: 1. Proteosomalt 2. Lysosomalt/ via Autofagi Thalidomide Bortezomib 15

16 Protein turnover as a target for therapy of multiple myeloma? protein synthesis, e.g. Immunoglobulins protein misfolding, aggregates autophgy lysosomal degradation proteosomal degradation? Bortezomib 16

17 KG Jebsen Center for Myeloma Research: 1. Biobank and clinical studies (PI: Anders Waage) 2. Classification of myeloma (PIs: Magne Børset/Anders Sundan) 3. Inflammation as driving force for survival of myeloma cells (PI: Terje Espevik) 4. Inflammation as driving force for the bone disease of multiple myeloma (PI: Therese Standal) Geir Slupphaug, IKM (classification), Marit Otterlei, IKM (novel treatments), Geir Bjørkøy, HiST(inflammation) og Øyvind Hjertner, St.Olavs Hospital (clinical studies) KREFTFORENINGEN 17

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