Project ID CM-HD2023_39

ThemeCM-HD

Co Supervisor 1A Comprehensive Cancer Centre/ CPS/ FOLSMWebsite

Co Supervisor 1B Comprehensive Cancer Centre/ CPS/ FOLSMWebsite

Early Detection and Prevention of Therapy-Related Myeloid Neoplasia in Cancer Survivors

Myelodysplastic syndromes and acute myeloid leukaemia (MDS/AML) are closely related blood cancers. A subtype of MDS/AML with DNA-damage repair pathway (DDRp) gene mutations (especially TP53) and complex aneuploidal karyotype (CK-MDS/AML) is incurable with median survival <1 year. However, it may be possible to identify at-risk patients earlier and offer better therapies. Clonal haematopoiesis (CHIP), when healthy individuals have somatic mutations in bone marrow (BM) and blood, is a risk factor for MDS/AML. ~10% of CHIP individuals have mutations in DDRp genes, especially TP53 and its regulator PPM1D, and are at high risk of MDS/AML. Furthermore, cancer patients who received DNA-damaging chemo/radiotherapy are also at increased risk of therapy-related MDS/AML, the majority of which have DDRp mutations. A hypothesis is that DDRp mutant haematopoietic stem progenitor cells (HSPCs) have disrupted apoptosis, enhanced survival and genomic instability, gain clonal advantage over unmutated HSPCs and have increased propensity to transform to MDS/AML. Median time from detecting CHIP DDRp-mutations to diagnosis of MDS/AML is 5 years, but emergence of additional mutations, aneuploidy, and changes in HSPC gene expression may occur beforehand at a ‘pre-leukaemic’ stage. These molecular changes may contribute to clonal expansion and evolution. As part of CHIP population study, we are screening healthy individuals and cancer patients for mutations and have already biobanked BM from 9 DDRp-mutant CHIP individuals. We will also access TP53/PPM1D-mutant MDS/AML samples from our biobank. Objectives: 1. AIM 1. Characterise HSPC and immune populations in TP53/PPM1D-mutant CHIP using single cell multi-omic methods. 2. AIM 2. Study how transcriptomes of these populations change from CHIP to MDS/AML to try to identify novel biomarkers that predict disease evolution from CHIP. 3. AIM 3. Test utility of TP53-reactivating drugs or PPM1D silencing to restoring normal HSPC biology in DDRp-mutant CHIP HSPCs.

One representative publication from each co-supervisor:

• Quek L, David, Muriel., Kennedy, A., Metzner, M., Amatangelo, M., Macbeth, K., De Botton, S., Levine, R., Thakurta, A., Penard-Lacronique, V., Vyas, P. Clonal heterogeneity in Differentiation Response and Resistance to AG-221 in IDH2m AML. Nature Medicine 2018; 24(8):1167-77.

• Abdul-Jawad, S., Baù, L., Alaguthurai, T., Del Molino Del Barrio, I., Laing, A. G., Hayday, T. S., Monin, L., Muñoz-Ruiz, M., McDonald, L., Francos Quijorna, I., McKenzie, D., Davis, R., Lorenc, A., Chan, J. N. E., Ryan, S., Bugallo-Blanco, E., Yorke, R., Kamdar, S., Fish, M., Zlatareva, I. & 31 others, , Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients 8 Feb 2021, In: CANCER CELL. 39, 2, p. 257-275.e6