Figure 2. HSPC-like leukemic blasts are... | American Society of Hematology

Figure 2.

$HSPC-like leukemic blasts are commonly observed across high-risk acute leukemias. (A) Fraction of leukemic blasts projected as stem/progenitor-like cells based on scRNA-seq in 4 leukemia subtypes. (B) Genomic tracks of scATAC-seq signal at CD34 (left) and KIT (right) loci in stem/progenitor-like and lineage-like leukemic blasts. Cis-regulatory elements are highlighted in yellow. (C) Fractions of mutant cells detected in HSPC-like, lineage-like blasts, and healthy cells based on 9 recurrent mutations (supplemental Table 4). Mutations in single cells were identified using the Genotyping of Transcriptomes assay. Patient IDs are added in front of the mutation name. (D) Percentage of BM replacement by leukemia blasts in 3 PDX models: T-myeloid MPAL (HSPC-like PDXs n = 4; lineage-like PDXs n = 2; left), ETP-ALL (HSPC-like PDXs n = 2; lineage-like PDXs n = 2; middle), and B-ALL (HSPC-like PDXs n = 8; lineage-like PDXs n = 8; right). Sorted cells (HSPC-like or lineage-like; supplemental Figure 4D-F) were used for the transplant experiments. (E,G) UMAPs show the projections of PDX cells derived from sorted HSPC-like (left) and lineage-like (right) primary leukemic blasts from B-ALL (E) and ETP-ALL (G). Gray dots represent cells from HDs, blue dots cells from HSPC-like derived PDX, and red dots cells from lineage-like derived PDX. (F,H) Fractions of PDX cells projected to particular populations for B-ALL (HSPC-like-derived PDXs n = 8, lineage-like-derived PDXs n = 8) (F) and ETP-ALL (HSPC-like-derived PDXs n = 2; lineage-like-derived PDXs n = 2) (H). Left, HSPC-like; middle, CLP-like; right, lineage-like. P values were computed using the Student t test. (I) Stemness gene signature scores for stem/progenitor-like and lineage-like leukemic blasts in all subtypes. Scores were calculated using AUCell. P values were computed using the Student t test. ∗∗P < .001; ∗∗∗P < .0001. (J-K) Box plots of Shannon entropy scores computed on the basis of scRNA-seq (J) and scATAC-seq (K) projected populations in each patient. Samples with high HSPC-like percentages represented the top 50% of HSPC-like fractions in each disease group, whereas samples with low HSPC-like percentages represented the bottom 50% of HSPC-like fractions in each disease group. P values were computed using the Student t test. ∗P < .05; ∗∗∗∗P < .0001. BM, bone marrow; B-M, B-myeloid; CLP, common lymphoid progenitor; n.s., not significant; T-M, T-myeloid; UMAP, Uniform Manifold Approximation and Projection.$

HSPC-like leukemic blasts are commonly observed across high-risk acute leukemias. (A) Fraction of leukemic blasts projected as stem/progenitor-like cells based on scRNA-seq in 4 leukemia subtypes. (B) Genomic tracks of scATAC-seq signal at CD34 (left) and KIT (right) loci in stem/progenitor-like and lineage-like leukemic blasts. Cis-regulatory elements are highlighted in yellow. (C) Fractions of mutant cells detected in HSPC-like, lineage-like blasts, and healthy cells based on 9 recurrent mutations (supplemental Table 4). Mutations in single cells were identified using the Genotyping of Transcriptomes assay. Patient IDs are added in front of the mutation name. (D) Percentage of BM replacement by leukemia blasts in 3 PDX models: T-myeloid MPAL (HSPC-like PDXs n = 4; lineage-like PDXs n = 2; left), ETP-ALL (HSPC-like PDXs n = 2; lineage-like PDXs n = 2; middle), and B-ALL (HSPC-like PDXs n = 8; lineage-like PDXs n = 8; right). Sorted cells (HSPC-like or lineage-like; supplemental Figure 4D-F) were used for the transplant experiments. (E,G) UMAPs show the projections of PDX cells derived from sorted HSPC-like (left) and lineage-like (right) primary leukemic blasts from B-ALL (E) and ETP-ALL (G). Gray dots represent cells from HDs, blue dots cells from HSPC-like derived PDX, and red dots cells from lineage-like derived PDX. (F,H) Fractions of PDX cells projected to particular populations for B-ALL (HSPC-like-derived PDXs n = 8, lineage-like-derived PDXs n = 8) (F) and ETP-ALL (HSPC-like-derived PDXs n = 2; lineage-like-derived PDXs n = 2) (H). Left, HSPC-like; middle, CLP-like; right, lineage-like. P values were computed using the Student t test. (I) Stemness gene signature scores for stem/progenitor-like and lineage-like leukemic blasts in all subtypes. Scores were calculated using AUCell. P values were computed using the Student t test. ∗∗P < .001; ∗∗∗P < .0001. (J-K) Box plots of Shannon entropy scores computed on the basis of scRNA-seq (J) and scATAC-seq (K) projected populations in each patient. Samples with high HSPC-like percentages represented the top 50% of HSPC-like fractions in each disease group, whereas samples with low HSPC-like percentages represented the bottom 50% of HSPC-like fractions in each disease group. P values were computed using the Student t test. ∗P < .05; ∗∗∗∗P < .0001. BM, bone marrow; B-M, B-myeloid; CLP, common lymphoid progenitor; n.s., not significant; T-M, T-myeloid; UMAP, Uniform Manifold Approximation and Projection.

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