Page 200 - Haematologica March 2020

H. Kuusanmäki et al.
BCL2 or BCL-xL gene expression within FAB subgroups (Online Supplementary Figure S7). AML samples with RUNX1T1-RUNX1T1 fusions showed significantly differ- ent gene expression exclusively in the M2 subgroup while samples with MLL or CBFB-MYH11 fusions showed sig- nificantly different gene expression exclusively in the M4 subgroup (Figure 5C, Online Supplementary Table S5). Particularly, M4 samples with MLL fusions had high BCL2 but low MCL1 expression levels compared to other M4 samples. To assess whether major signal transduction pathways are differentially active in FAB subtypes, we performed gene set enrichment analysis (GSEA). The
analysis revealed significant enrichment of gene sets asso- ciated with inflammatory signaling and IL6/JAK/STAT pathway in M4/5 AML (Figure 5D-E, Online Supplementary Table S6).
To study whether ex vivo venetoclax response is associ- ated with differentiation markers and BCL2 family expres- sion, we analyzed the published Beat AML data set which includes data from 562 AML patients.22 Supporting our previous findings, samples that had high expression of monocytic/granulocytic cell markers (CD14, CD11b, CD86, CD68) were resistant to venetoclax (Figure 5F). High BCL2 expression was associated with venetoclax
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Figure 4. Mononuclear cell (MNC) fraction sensitivity to venetoclax is dependent on FAB subtypes. (A) Venetoclax drug sensitivity score (DSS) values of AML samples with different French-American-British (FAB) subtypes from an earlier pub- lished data set, and (B) from the present data set both measuring MNC fraction sensitivity with CTG based cell viability assay. (C) Blast- specific venetoclax sensitivity of diagnosis samples in FAB sub- groups measured by FC from the present data set. (D) Blast-specific venetoclax sensitivity in different FAB subgroups measured by FC including chemorefractory and relapse samples. (E) Comparison of venetoclax DSS values between diagnosis, relapse and chemore- fractory samples (induction resist- ant n=3, azacytidine resistant n=2). Black lines represent the mean of each subgroup. P-values calculated with the Kruskal-Wallis (and Dunn’s) tests. FC: flow cytometric.
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haematologica | 2020; 105(3)