Fig. 5: Subclonal NOTCH1 mutations additively contribute to differentiation toward the T-specified state. | Nature Cancer

Fig. 5: Subclonal NOTCH1 mutations additively contribute to differentiation toward the T-specified state.

From: A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia

Fig. 5

a, Identification of n = 7 subclonal NOTCH1 mutations in n = 3 MRD-negative participants with BMP-like associated fusion drivers. b, Left: experimental workflow for detection of NOTCH1-mut leukemic blasts in scRNA-seq libraries through GoT. cb, cell bar code; umi, unique molecular identifier. c, Summary statistics from n = 9,314 genotyped cells from seven independent GoT experiments. P values from a chi-square test are shown (***P < 2.2 × 10−16). Right: expression of NOTCH1-mut UMIs amongst ETP blast and non-ETP blast populations in scRNA-seq data. P values from a two-sided Mann–Whitney test are shown (***P < 2.2 × 10−16). The median of both populations and 90th percentile of UMI reads in non-blast populations are indicated within each violin plot. frac, fraction. d, GoT detection of 7/7 mut transcripts determined from bulk WES and WGS (n = 7,754 cells; n = 5,625 NOTCH1-mut: PAVLKA, n = 3,352; PAWGWD, n = 2,273). e, Fraction of BMP-like and T-specified cells within NOTCH1-mut cells (n = 5,625 cells: PAVLKA, n = 3,352; PAWGWD, n = 2,273). f, Detection of n = 1,971 cells harboring two unique NOTCH1 mutations within leukemic blasts from PAVLKA (n = 1,649) and PAWGWD (n = 322). g, Association of BMP-like and T-specified signature scores with NOTCH1 mutation dosage in single cells. Cells are binarized into zero (WT; PAVKLA, n = 134; PAWGWD, n = 2,365), one (PAVKLA, n = 1,545; PAWGWD, n = 1,739) and two (PAVKLA, n = 1,649; PAWGWD, n = 322) mutations. P values from a two-sided Mann–Whitney test are shown. h, Association of NOTCH1-mut transcript expression and BMP-like and T-specified signatures (n = 7,754 genotyped single cells from PAWGWD and PAVLKA are plotted). The Pearson correlation coefficient and P value for Pearson’s product moment are indicated to the top right. i, Transcriptome similarity of GSI-treated DND-41 T-ALL cells (n = 3 per condition) with T cell developmental stages identified in scRNA-seq data. j, Upregulation of BMP-like transcriptomic signature in GSI-treated DND-41 (GSE173872, n = 3 per condition) and THP-6 (near-ETP; GSE138659, n = 3 per condition) T-ALL cell lines. Cell lines were scored using the 119 BMP-like signatures established in Fig. 2. P values from a two-sided t-test are shown.

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