Abstract 4524: Targeting Bcl-2 family proteins in adult T-cell leukemia/lymphoma: in vitro and in vivo effects of a novel Bcl-2 family inhibitor, ABT-737

Kunami, Naoko; Ishitsuka, Kenji; Yotsumoto, Fusanori; Ishikawa, Chie; Katsuya, Hiroo; Shibata, Shigeki; Tanji, Hiroe; Takeshita, Morishige; Mori, Nozomu; Miyamoto, Shingo; Kuroki, Masahide; Tamura, Kazuo

doi:10.1158/1538-7445.am10-4524

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“…Subtype analysis showed that B/My MPAL blast-specific genes included AUTS2 , M EF2A , RB1CC1 , and HBEGF , whereas T/My MPAL blasts overexpressed PTEN , ESYT2 , KMT2C , and PTGG1IP . Heparin-binding epidermal growth factor-like growth factor ( HBEGF ) has been implicated in several cancers including leukemias as an inducer of tumor growth [ 65 – 67 ], and has previously been targeted in various cancers with small molecule inhibitors [ 67 – 69 ]. PTEN is typically considered a tumor suppressor gene, with inactivation leading to the development of T-ALL and AML [ 70 , 71 ], thus the significance of PTEN overexpression in T/My blasts needs further exploration.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing distinctly characterizes the wide heterogeneity in pediatric mixed phenotype acute leukemia

Mumme,

Raikar,

Bhasin

et al. 2023

Genome Med

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Background Mixed phenotype acute leukemia (MPAL), a rare subgroup of leukemia characterized by blast cells with myeloid and lymphoid lineage features, is difficult to diagnose and treat. A better characterization of MPAL is essential to understand the subtype heterogeneity and how it compares with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Therefore, we performed single-cell RNA sequencing (scRNAseq) on pediatric MPAL bone marrow (BM) samples to develop a granular map of the MPAL blasts and microenvironment landscape. Methods We analyzed over 40,000 cells from nine pediatric MPAL BM samples to generate a single-cell transcriptomic landscape of B/myeloid (B/My) and T/myeloid (T/My) MPAL. Cells were clustered using unsupervised single-cell methods, and malignant blast and immune clusters were annotated. Differential expression analysis was performed to identify B/My and T/My MPAL blast-specific signatures by comparing transcriptome profiles of MPAL with normal BM, AML, and ALL. Gene set enrichment analysis (GSEA) was performed, and significantly enriched pathways were compared in MPAL subtypes. Results B/My and T/My MPAL blasts displayed distinct blast signatures. Transcriptomic analysis revealed that B/My MPAL profile overlaps with B-ALL and AML samples. Similarly, T/My MPAL exhibited overlap with T-ALL and AML samples. Genes overexpressed in both MPAL subtypes’ blast cells compared to AML, ALL, and healthy BM included MAP2K2 and CD81. Subtype-specific genes included HBEGF for B/My and PTEN for T/My. These marker sets segregated bulk RNA-seq AML, ALL, and MPAL samples based on expression profiles. Analysis comparing T/My MPAL to ETP, near-ETP, and non-ETP T-ALL, showed that T/My MPAL had greater overlap with ETP-ALL cases. Comparisons among MPAL subtypes between adult and pediatric samples showed analogous transcriptomic landscapes of corresponding subtypes. Transcriptomic differences were observed in the MPAL samples based on response to induction chemotherapy, including selective upregulation of the IL-16 pathway in relapsed samples. Conclusions We have for the first time described the single-cell transcriptomic landscape of pediatric MPAL and demonstrated that B/My and T/My MPAL have distinct scRNAseq profiles from each other, AML, and ALL. Differences in transcriptomic profiles were seen based on response to therapy, but larger studies will be needed to validate these findings.

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