Johanna Ungerstedt Associate professor of Hematology Specialist in

Johanna Ungerstedt Associate professor of Hematology Specialist in Internal Medicine and Hematology Research Group leader HERM , Inst for Medicine, Huddinge Karolinska Institute Karolinska University Hospital

Myeloida celler Lymfoida celler

Forskningsområden översikt KML KOAGULATION LYMFO M KLL OVANLIGA DIAGNOSER ALLOGEN STAMCELLSTRANSPL ANTATION STAMCELLER CYTOSTATIKA EFFEKTER OCH RESISTENS AKUT LEUKEMI MDS MYELO M INFEKTIONER HOS IMMUNSUPPRIM ERADE

CYTOSTATIKA EFFEKTER OCH RESISTENS Moustafa Hassan Musmodell för att titta på cytostatikas effekter på olika organ Freidoun Albertioni Farmakokinetik, dostitrering, resistensmekanismer Moderna antitumörläkemedel PD-1 hämmare BCL 2 hämmare Brutons kinas hämmare Små molekyl hämmare TKI JAK 2 hämmare vid MPN

LYMFOM KLL Björn Wahlin, Karin Ekström Smedby Stadieindelning. Epidemiologi, nya prognostiska markörer, läkemedelsstudier Nya läkemedel, spännande studier, hett ämne! Nya NOAK/DOAK KOAGULATION

ALLOGEN STAMCELLSTRANSPL ANTATION GVH Mesenkymala stamceller Riktade T celler mot infektioner Dr. E. Donnall Thomas, MD, won the Nobel Prize in 1990 BMT STAMCELLER Sten Eirik Jacobsen Petter Woll INFEKTIONER HOS IMMUN SUPPRIMERADE Per Ljungman Diagnostik, profylax och behandling av infektionskomplikationer hos allo patienter. Herpesvirus. Vaccinationsstrategier. EBMT.

MYELOM Cytogenetik prognostisk betydelse Kliniska studier med läkemedels kombinationer och nya läkemedel Expansion av NK celler ex vivo att ge tillbaka till patient

Myeloida maligniteter AKUT LEUKEMI MDS Sören Lehmann, Stefan Deneberg Normalrisk AML Åsa Derolf, Magnus Björkholm Flödescytometri MRD Johanna Ungerstedt Epigenetik Eva Hellström Lindberg Stamceller, 5 q- , kliniska studier NMDS, Biobank Martin Jädersten 5 qsyndrom

KML § Glivec (imatinibmesylat) § Glivec är godkänt för behandling av patienter med nydiagnostiserad Philadelphiakromosom- (Bcr-Abl)-positiv (Ph+) KML. § Imatinib =intracellulär signaltransduktionshämmare hämmar cytoplasmatiska tyrosinkinas som är ett resultat av den kromosomtranslokation som orsakar kronisk myeloisk leukemi. Glivec är således det första godkända läkemedlet av en ny typ av anticancerläkemedel. § IMATINIB GLIVEC § DASATINIB SPRYCEL § NILOTINIB TASIGNA

STOPPSTUDIER! KML

Cumulative relative survival in AML stratified by calendar period. Åsa Rangert et al Blood. 2009 Apr 16; 113(16)

Different methylation in normal progenitors and AML. (A) Two-way unsupervised hierarchical analysis (Pearson correlation, complete clustering) of differentially methylated Cp. G residues (n = 2764) between CN-AML and myeloid progenitor cells. Deneberg S et al. Blood 2011; 118: 5573 -5582 © 2011 by American Society of Hematology

Johanna Ungerstedt Epigenetik

Ungerstedt research group: Epigenetics in CMML and mast cell disease Katarina Lyberg Post doc Hani Abdulkadir Ali Ph. D student Jennine Grootens, Ph. D student (JU co supervisor) Maritha Kumlin, Ph. D student (JU co supervisor) Annika Voigt, Masters student Deepika Nair Ph. D student Prajakta Khalkar, Post Doc Igor Schliemann, MD, Project student Matilda Kjellander Ph. D student Namn Efternamn Kajsa Ax, Research BMA, Responsible for Mastocytosis Bíobank 15

Johanna Ungerstedt -what took so long? doc t s po I. K r 2. 1 r n ild n d. l i s ar Ch 2. Ch die e. u O t y s 1 ÄF 8 m oc nr D k 1 L r h o ik st d es. P Y i v 1 s d r ew köld. Po n stu N f. k l. a a s o y c m r e 3 c l n c D o i r r P x 2 o den r h st d d b. h n Ö c e P c e k e , i d i o M d il Sp Po AT Stoc Res MD Ass Ch Stu 1994 1998 Course mates Get MD degree Namn Efternamn 2003 2004 2005 2007 2008 Course mates become Specialists 2011 2014 2015 2016 Specialist Hematology After 22 years 16

Pros and cons of combined career as doctor and scientist + § 50% Clinical Research Position (Cancerfonden) § I control and plan my time § Committee work, SFH, EHA, KI CSTP, travel grants and other grant committees, organizing conferencesl § Defense committees, opponent § Travel, conferences, give talks, international collaborations Namn Efternamn § § § - 50% clinic, slow progress in residency that takes forever Bad progress in salary Never become a ”real doctor”, no control over how time is planned in the clinic, always in rotation at other clinic. Difficult to run clinical trials during residency Difficult to manage research and supervise Ph. D students during clinical duty 17

How to choose specialization? § If you are primarily interested in research, it is probably wise to choose a specialization that is named ”clinical” something. These specializations typically do not contain patients, thus it is easier to plan your time… § I happened to run into Hematology when deciding for subspecialization within Internal Medicine. Advantage: In hematology, the step from bench to bedside is very short, because mortality in our diseases is high Disadvantage: patients are very sick, you need to be constantly alert and keep a look out for your patients! Namn Efternamn 18

Hematology § § Acute myeloid leukemia (overall 5 year survival 20%) Myelodysplastic syndromes (median survival 0, 4 -5, 7 y depends on type) Chronic myeloid leukemia and myeloproliferative disease (long survival) Systemic mastocytosis (varying survival) § Work in outpatient clinic including answering referral requests § Work in inpatient clinic in the Hematology ward, very sick patients with ongoing chemotherapy, neutropenic infections. § On call duty ”bakjour” Namn Efternamn 19

Systemic mastocytosis, a rare disease same genotype (D 816 V mutation) but great variation in phenotype Prognosis Expected US survival Indolent SM, Aggressive SM n= 342 Ken-Hong Lim et al. Blood 2009; 113: 5727 -5736 Symptoms of mediator release: itching, severe diarrhea, palpitations, anaphylactic shock, food and drug reactions, fatigue, bone pain, osteoporosis

Center of Excellence Systemic Mastocytosis Karolinska Clinical allergology Endocrinology Dermatology Gastroenterology Psychiatry Clinical Immunology Pathology Hematology Namn Efternamn 21

SAHA decreases cell surface KIT, m. RNA and protein levels in HMC-1. 2 SM cell line and kills patient tumor cells Healthy 1 Healthy 2 ISM ASM MCL Lyberg et al, Oncotarget 2017 Namn Efternamn 22

Experimental setup 50 000 cells HMC 1. 2 MC Culture DMSO & SAHA 6 h & 24 h Chromatin immunoprecipitation assay (H 3 K 27 ac, H 3 K 4 me 3 & H 3 K 27 me 3) FACS sorting: DMSO (CD 117 high) SAHA (CD 117 high &low) ATAC RNA isolation High-throughput Sequencing Bioinformatic analysis pipeline: QC Map to genome Filter for high-quality aligned reads remove duplicates count transcripts(RNA-seq)/call peaks (Ch. IP-seq, ATAC-seq) Data normalization Downstream analysis Name Surname 03 November 2020 23

HDACi shut down KIT and downstream signaling pathways DMSO SAHA H 3 K 27 ac (log. FC<-2) H 3 K 4 me 3 (log. FC<-1) KIT GO analysis RNA seq: 6 h, 24 h Name Surname 03 November 2020 24

Ph. D student path Start Ph. D

Combined Career Doctor and Scientist Obstacles: Clinical work Children Clinical boss does not understand research, Research boss does not understand clinical work Start MD, Ph. D Specialist

Acknowledgements Ungerstedt lab: Hani Abdulkadir Ali Deepika Nair Matilda Kjellander Katarina Lyberg Igor Schliemann Annika Voigt Kajsa Ax Prajakta Khalkar Maritha Kumlin and Jennine Grootens MBB Biochemistry: Aristi Fernandes HERM: Eva Hellström Lindberg ECNM: Peter Valent Center of Excellence Karolinska: Gunnar Nilsson Birgitta Sander Theo Gülen RADIUMHEMMETS FORSKNINGSFONDER Namn Efternamn 27