Genetic changes in

MDS

Apoptosis

Differentiation

Asymptomatic,IPSS low Low/Int-1

Symptomatic,IPSS Int-2/High Risk

BM function

Greenberg, Blood 1997, Malcovati,JCO 2009,Greenberg Blood 2012

TransfusionTransfusion

Proliferation and Blasts

IPSS

Spectrum of MDS

Gross genomic changes are detected by cytogenetics

MDS cytogenetic studies

ATG AAG TTA CAT CAT TGG AAA TTT GAT TGA

Met Lys Leu His His Trp Lys Phe Asp *

ATG AAG TTA CAT GAT TGA AAA TTT GAT TGA

Met Lys Leu His Asp * Lys Phe Asp *

Small genetic changes can only be detected at the molecular level.

Mutations alter proteins

RUNX1ETV6

WT1 PHF6

GATA2

DNMT3AEZH2

ASXL1

IDH1 & 2

UTX

TP53

Transcription FactorsTyrosine Kinase Pathway

Epigenetic Dysregulation

SF3B1

Splicing Factors

JAK2

NRAS

BRAF

KRAS

RTK’s

PTPN11

CohesinsGNAS/GNB1

RNA helicasesCBL

NPM1

ATRX

Others

SRSF2

U2AF1ZRSF2

SETBP1

SF1SF3A1

PRPF40BU2AF2

PRPF8

BCOR

TET2

Point Mutations in MDS

EP300

Haferlach et al., Leukemia. 2014 Feb;28(2):241-7

Only 5 genes are mutated in >10% of patients

Many mutations are very rare

Target present on the KCH panel

KCH: Myeloid Gene Panel (MGP)

Transcription factors and cell cycle regulators

RUNX1 TP53GATA2ETV6CEBPANPM1

Spliceosome component SF3B1U2AF1SRSF2ZRSR2

Epigenetic modifications TET2IDH1IDH2DNMT3AKDM6AASXL1EZH2

Signaling

NRASKRASFLT3CBLJAK2KIT

Cohesin complex

STAG2

24 genes mutations panel:

Research use only: clinical importance is yet to be determined

• Integrating genomic analysis into diagnostic, prognostic and therapeutic systems for patients.

–The challenge for the laboratory

Lenalidomide (Revlimid)TP53mut do not achieve complete cytogenetic response in del5q MDS (Jadersten JCO, Austin Kulasekararaj BJH)

5’Azacytidine (Vidaza)• TET2mut may respond better• TET2mut and DNMT3Amut may respond better• ASXL1 and SF3B1 status also modulate response

Therapy response / outcome

Finally

• Genetic testing is more widely available:

– Cheaper, simpler, faster

• Mutations help in the certainty of diagnosis.

• Incorporation into prognostic models such as

IPSS

• The era of biomarker-based therapy may not

be too distant

Department of Hematological Medicine, King’s College London

Prof G MuftiProf Judith MarshDr Austin KulaesekararajDr Robin Ireland

LMH laboratory KCH:Dr Steve BestDr Aytug KizilorsSara RibeiroTashna Smith

Acknowledgments