A transgenic mouse model of Down syndrome acute lymphoblastic leukemia identifies targetable vulnerabilities

Haematologica · 2024-07-25 · 3 citations

Not available.

Table S2 from Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

2023-03-31

<p>Cluster marker genes of Single cell RNA-seq</p>

Table S1 from Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

2023-03-31

<p>NGS data statistics</p>

Table S4 from Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

2023-03-31

<p>Differentially accessible regions</p>

Data from Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

2023-03-31

<div>Abstract<p>Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that Tet2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8<sup>+</sup> T-cell activation. Furthermore, the ETS family of transcription factors contributed to augmented CD8<sup>+</sup> T-cell function following Tet2 depletion. Overall, our study establishes that Tet2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that Tet2 inactivation could promote antitumor immunity to suppress tumor growth.</p>Significance:<p>This study suggests that ablation of TET2<sup>+</sup> from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.</p></div>

Data from Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

2023-03-31

<div>Abstract<p>Inactivation of tumor-infiltrating lymphocytes (TIL) is one of the mechanisms mitigating antitumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the antitumor activity of TILs with an efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-sequencing analysis suggested that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-sequencing analysis showed that Tet2 ablation reshapes chromatin accessibility and favors binding of transcription factors geared toward CD8<sup>+</sup> T-cell activation. Furthermore, the ETS family of transcription factors contributed to augmented CD8<sup>+</sup> T-cell function following Tet2 depletion. Overall, our study establishes that Tet2 constitutes one of the epigenetic barriers that account for dysfunction of TILs and that Tet2 inactivation could promote antitumor immunity to suppress tumor growth.</p>Significance:<p>This study suggests that ablation of TET2<sup>+</sup> from TILs could promote their antitumor function by reshaping chromatin accessibility for key transcription factors and enhancing the transcription of genes essential for antitumor activity.</p></div>

Epichaperome inhibition targets <i>TP53-</i>mutant AML and AML stem/progenitor cells

Blood · 2023-06-20 · 26 citations

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. PU-H71 effectively suppressed cell intrinsic stress responses and killed AML cells, primarily by inducing apoptosis; targeted TP53-mutant stem/progenitor cells; and prolonged survival of TP53-mutant AML xenograft and patient-derived xenograft models, but it had minimal effects on healthy human BM CD34+ cells or on murine hematopoiesis. PU-H71 decreased MCL-1 and multiple signal proteins, increased proapoptotic Bcl-2-like protein 11 levels, and synergized with BCL-2 inhibitor venetoclax in TP53-mutant AML. Notably, PU-H71 effectively killed TP53-WT and -mutant cells in isogenic TP53-WT/TP53-R248W Molm13 cell mixtures, whereas MDM2 or BCL-2 inhibition only reduced TP53-WT but favored the outgrowth of TP53-mutant cells. Venetoclax enhanced the killing of both TP53-WT and -mutant cells by PU-H71 in a xenograft model. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation.

Table S1 from Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

2023-03-31

&lt;p&gt;NGS data statistics&lt;/p&gt;

Table S4 from Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

2023-03-31

&lt;p&gt;Differentially accessible regions&lt;/p&gt;

Suppl Figures from Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes

2023-03-31

&lt;p&gt;Supplemental Figures 1-5.&lt;/p&gt;