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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