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Genetic changes in MDS Spectrum of MDS Asymptomatic,IPSS low Low/Int-1 Symptomatic,IPSS Int-2/High Risk Transfusion Differentiation Proliferation and Blasts Apoptosis IPSS Greenberg, Blood 1997, Malcovati,JCO 2009,Greenberg Blood 2012 Gross genomic changes are detected by cytogenetics MDS cytogenetic studies Mutations alter proteins Small genetic changes can only be detected at the molecular level. Met Lys Leu His His Trp Lys Phe Asp * ATG AAG TTA CAT CAT TGG AAA TTT GAT TGA ATG AAG TTA CAT GAT TGA AAA TTT GAT TGA Met Lys Leu His Asp * Lys Phe Asp * Point Mutations in MDS Tyrosine Kinase Pathway Transcription Factors Others JAK2 RUNX1 TP53 KRAS BRAF ETV6 NRAS PTPN11 CBL EP300 WT1 DNMT3A PHF6 Splicing Factors EZH2 SF3B1 PRPF40B U2AF2 UTX ASXL1 ATRX ZRSF2 U2AF1 SETBP1 TET2 NPM1 Cohesins GNAS/GNB1 BCOR RNA helicases RTK’s Epigenetic Dysregulation IDH 1&2 GATA2 SRSF2 SF1 PRPF8 SF3A1 Many mutations are very rare Haferlach et al., Leukemia. 2014 Feb;28(2):241-7 Only 5 genes are mutated in >10% of patients Target present on the KCH panel KCH: Myeloid Gene Panel (MGP) 24 genes mutations panel: Transcription factors and cell cycle regulators RUNX1 TP53 GATA2 ETV6 CEBPA NPM1 Spliceosome component SF3B1 U2AF1 SRSF2 ZRSR2 Epigenetic modifications TET2 IDH1 IDH2 DNMT3A KDM6A ASXL1 EZH2 Signaling NRAS KRAS FLT3 CBL JAK2 KIT Research use only: clinical importance is yet to be determined Cohesin complex STAG2 – The challenge for the laboratory • Integrating genomic analysis into diagnostic, prognostic and therapeutic systems for patients. Therapy response / outcome 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 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 Acknowledgments Department of Hematological Medicine, King’s College London Prof G Mufti Prof Judith Marsh Dr Austin Kulaesekararaj Dr Robin Ireland LMH laboratory KCH: Dr Steve Best Dr Aytug Kizilors Sara Ribeiro Tashna Smith
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