Genetic changes in MDS Spectrum of MDS Asymptomatic

Genetic changes in MDS

Spectrum of MDS Asymptomatic, IPSS low Low/Int-1 BM function Symptomatic, IPSS Int-2/High Risk ion 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 Trp Lys Phe Asp * ATG AAG TTA 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 JAK 2 RUNX 1 TP 53 KRAS BRAF NRAS PTPN 11 CBL EP 300 WT 1 DNMT 3 A PHF 6 Splicing Factors EZH 2 SF 3 B 1 U 2 AF 2 UTX ASXL 1 ATRX ZRSF 2 U 2 AF 1 SETBP 1 TET 2 NPM 1 Cohesins GNAS/GNB 1 BCOR RNA helicases RTK’s Epigenetic Dysregulation IDH 1&2 ETV 6 GATA 2 SRSF 2 SF 1 PRPF 40 B PRPF 8 SF 3 A 1

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 RUNX 1 TP 53 GATA 2 ETV 6 CEBPA NPM 1 Spliceosome component SF 3 B 1 U 2 AF 1 SRSF 2 ZRSR 2 Epigenetic modifications TET 2 IDH 1 IDH 2 DNMT 3 A KDM 6 A ASXL 1 EZH 2 Signaling NRAS KRAS FLT 3 CBL JAK 2 KIT Research use only: clinical importance is yet to be determined Cohesin complex STAG 2

– The challenge for the laboratory • Integrating genomic analysis into diagnostic, prognostic and therapeutic systems for patients.

Therapy response / outcome Lenalidomide (Revlimid) TP 53 mut do not achieve complete cytogenetic response in del 5 q MDS (Jadersten JCO, Austin Kulasekararaj BJH) 5’Azacytidine (Vidaza) • TET 2 mut may respond better • TET 2 mut and DNMT 3 Amut may respond better • ASXL 1 and SF 3 B 1 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

Acknowledgme nts 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