KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress

Issa, Nancy; Bjeije, Hassan; Wilson, Elisabeth R.; Krishnan, Aishwarya; Dunuwille, Wangisa M.B.; Parsons, Tyler; Zhang, Christine; Han, Wentao; Young, Andrew L.; Ren, Zhizhong; Ge, Kai; Wang, Eunice S.; Weng, Andrew P.; Cashen, Amanda F.; Spencer, David H.; Challen, Grant A.

doi:10.1038/s41375-023-01853-9

Cited by 6 publications

(4 citation statements)

References 46 publications

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“…3 B). A previous study highlighted KDM6B ’s crucial role in supporting NOTCH1 -driven T cell acute lymphoblastic leukemia [ 40 ]. The synergistic effect of NOTCH1 and KDM6B mutations therefore may accelerate lymphoma progression by activating oncogenic pathways via chromatin remodeling.…”

Section: Resultsmentioning

confidence: 99%

Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression

Chen,

Huang,

Hong

et al. 2024

Genome Med

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Background Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. Methods Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. Results Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0–C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. Conclusions The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine.

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Section: Resultsmentioning

confidence: 99%

Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression

Chen,

Huang,

Hong

et al. 2024

Genome Med

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“…Meanwhile, KDM6B is required to prevent apoptosis of NOTCH1-driven T-ALL. Therefore, targeting KDM6B might be an efficient therapeutic strategy for NOTCH1-induced T-ALL patients [ 29 ]. Other studies showed that transgenic deletion of interleukin-15 (IL-15) or IL-15 receptor alpha-chain generates T-ALL in NOD mice accompanied by increased NOTCH1 activation and impaired DNA repair capability.…”

Section: Resultsmentioning

confidence: 99%

An Update on Clinical Trials and Potential Therapeutic Strategies in T-Cell Acute Lymphoblastic Leukemia

Patel

Gao

Wang

2023

IJMS

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Current therapies for T-cell acute leukemia are based on risk stratification and have greatly improved the survival rate for patients, but mortality rates remain high owing to relapsed disease, therapy resistance, or treatment-related toxicities/infection. Patients with relapsed disease continue to have poor outcomes. In the past few years, newer agents have been investigated to optimize upfront therapies for higher-risk patients in the hopes of decreasing relapse rates. This review summarizes the progress of chemo/targeted therapies using Nelarabine/Bortezomib/CDK4/6 inhibitors for T-ALL in clinical trials and novel strategies to target NOTCH-induced T-ALL. We also outline immunotherapy clinical trials using monoclonal/bispecific T-cell engaging antibodies, anti-PD1/anti-PDL1 checkpoint inhibitors, and CAR-T for T-ALL therapy. Overall, pre-clinical studies and clinical trials showed that applying monoclonal antibodies or CAR-T for relapsed/refractory T-ALL therapy is promising. The combination of target therapy and immunotherapy may be a novel strategy for T-ALL treatment.

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“…It has been recently suggested that this effect relies on 'metabolic reservoirs' [40], which represent a pool of vital metabolites ready to be used by cancer cells. It has been reported that the Warburg effect in cancer cells generates an antiapoptotic extracellular microenvironment by elevating the extracellular lactate/pyruvate ratio, which desensitizes HepG2 cells toward apoptotic insult [41]. Indeed, dynamic metabolic changes characterize the heterogenous responses of Jurkat, TALL1, and the NOTCH-independent Loucy cells under a TEC-conditioned medium.…”

Section: Discussionmentioning

confidence: 99%

Thymic-Epithelial-Cell-Dependent Microenvironment Influences Proliferation and Apoptosis of Leukemic Cells

Patel,

Zhdanovskaya,

Sergio

et al. 2024

IJMS

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T-cell acute lymphoblastic leukemia (T-ALL) is a hematological cancer characterized by the infiltration of immature T-cells in the bone marrow. Aberrant NOTCH signaling in T-ALL is mainly triggered by activating mutations of NOTCH1 and overexpression of NOTCH3, and rarely is it linked to NOTCH3-activating mutations. Besides the known critical role of NOTCH, the nature of intrathymic microenvironment-dependent mechanisms able to render immature thymocytes, presumably pre-leukemic cells, capable of escaping thymus retention and infiltrating the bone marrow is still unclear. An important challenge is understanding how leukemic cells shape their tumor microenvironment to increase their ability to infiltrate and survive within. Our previous data indicated that hyperactive NOTCH3 affects the CXCL12/CXCR4 system and may interfere with T-cell/stroma interactions within the thymus. This study aims to identify the biological effects of the reciprocal interactions between human leukemic cell lines and thymic epithelial cell (TEC)-derived soluble factors in modulating NOTCH signaling and survival programs of T-ALL cells and TECs. The overarching hypothesis is that this crosstalk can influence the progressive stages of T-cell development driving T-cell leukemia. Thus, we investigated the effect of extracellular space conditioned by T-ALL cell lines (Jurkat, TALL1, and Loucy) and TECs and studied their reciprocal regulation of cell cycle and survival. In support, we also detected metabolic changes as potential drivers of leukemic cell survival. Our studies could shed light on T-cell/stroma crosstalk to human leukemic cells and propose our culture system to test pharmacological treatment for T-ALL.

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KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress

Cited by 6 publications

References 46 publications

Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression

Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression

An Update on Clinical Trials and Potential Therapeutic Strategies in T-Cell Acute Lymphoblastic Leukemia

Thymic-Epithelial-Cell-Dependent Microenvironment Influences Proliferation and Apoptosis of Leukemic Cells

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