TY - JOUR T1 - Longitudinal single-cell transcriptomics reveals distinct patterns of recurrence in acute myeloid leukemia JF - bioRxiv DO - 10.1101/2022.01.04.474929 SP - 2022.01.04.474929 AU - Yanan Zhai AU - Prashant Singh AU - Anna Dolnik AU - Peter Brazda AU - Nader Atlasy AU - Nunzio del Gaudio AU - Konstanze Döhner AU - Hartmut Döhner AU - Saverio Minucci AU - Joost Martens AU - Lucia Altucci AU - Wout Megchelenbrink AU - Lars Bullinger AU - Hendrik G. Stunnenberg Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/01/05/2022.01.04.474929.abstract N2 - The heterogeneity and evolution of AML blasts can render therapeutic interventions ineffective in a yet poorly understood patient-specific manner. To gain insight into the clonal heterogeneity of diagnosis (Dx) and relapse (Re) pairs, we employed whole-exome sequencing and single-cell RNA-seq to longitudinally profile two t(8;21) (AML1-ETO = RUNX1-RUNX1T1), and four FLT3-ITD AML cases.The single cell RNA data underpinned the tumor heterogeneity amongst patient blasts. The Dx-Re transcriptomes of high risk FLT3-ITD pairs formed a continuum from extensively changed in the absence of significantly mutational changes in AML-associated genes to rather similar Dx-Re pair of an intermediate risk FLT3-ITD. In one high risk FLT3-ITD pair, a pathway switched from an AP-1 regulated network in Dx to mTOR signaling in Re. The distinct AML1-ETO pairs comprise clusters that share genes related to hematopoietic stem cell maintenance and cell migration suggesting that the Re leukemic stem cell-like (LSC-like) cells probably evolved from the Dx LSC-like cells.In summary, our study revealed a continuum from drastic transcriptional changes to extensive similarities between respective Dx-Re pairs that are poorly explained by the well-established model of clonal evolution. Our results suggest alternative and currently unappreciated and unexplored mechanisms leading to therapeutic resistance and AML recurrence.Competing Interest StatementThe authors have declared no competing interest. ER -