Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma

Ishio, Takashi; Kumar, Sarvesh; Shimono, Joji; Daenthanasanmak, Anusara; Dubois, Sigrid; Lin, Yuquan; Bryant, Bonita R.; Petrus, Michael; Bachy, Emmanuel; Huang, Da Wei; Yang, Yandan; Green, Patrick L.; Hasegawa, Hiroo; Maeda, Masako; Goto, Hideki; Endo, Tomoyuki; Yokota, Takashi; Hatanaka, Kanako C.; Hatanaka, Yutaka; Tanaka, Shinya; Matsuno, Yoshihiro; Yang, Yibin; Hashino, Satoshi; Teshima, Takanori; Waldmann, Thomas A.; Staudt, Louis M.; Nakagawa, Masao

doi:10.1182/blood.2021012734

Cited by 28 publications

(15 citation statements)

References 41 publications

(52 reference statements)

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“…Recruitment of both BATF3 and IRF4 to this region was confirmed by ChIP-seq and ChIP-qPCR (Figures 3C, S3B and S3C) (Nakagawa et al ., 2018). BATF3 is known to alter the expression of ATL-associated genes in concert with IRF4 (Ishio et al, 2022; Nakagawa et al ., 2018). Thus, we next performed promoter assays using the identified region upstream of human TAp73 .…”

Section: Resultsmentioning

confidence: 99%

Reprogramming of lactate metabolism is linked to the oncogenesis of the virus-induced leukemia

Toyoda

Yasunaga

Arima

et al. 2022

Preprint

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Acceleration of glycolysis is a common trait of cancer. A key metabolite, lactate, is properly secreted from cancer cells, since its accumulation is toxic. Here, we report that a viral oncogene, HTLV-1 bZIP factor (HBZ), bimodally upregulates TAp73 to promote lactate excretion from adult T-cell leukemia-lymphoma (ATL) cells. HBZ protein binds to EZH2 and reduces its occupancy of the TAp73 promoter. Meanwhile, HBZ RNA activates TAp73 transcription via the BATF3-IRF4 machinery. TAp73 upregulates the lactate transporters MCT1 and MCT4. Inactivation of TAp73 leads to intracellular accumulation of lactate, inducing cell death in ATL cells. Furthermore, TAp73 knockout diminished development of inflammation in HBZ-transgenic mice. An MCT1/4 inhibitor, syrosingopine, decreased the growth of ATL cells in vitro and in vivo. MCT1/4 expression was positively correlated with TAp73 in many cancers, and their upregulations were associated with dismal prognosis. Activation of the TAp73-MCT1/4 pathway could be a common mechanism contributing to oncogenesis.

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Section: Resultsmentioning

confidence: 99%

Reprogramming of lactate metabolism is linked to the oncogenesis of the virus-induced leukemia

Toyoda

Yasunaga

Arima

et al. 2022

Preprint

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“…The results identified genes upregulated in leukemogenic T‐cells that are associated with cancer progression, including mTORC1 and MYC pathways driving proliferation and metabolic processes. The relationship between the mTOR complex and Myc has been the focus of various studies, 40–42 with some suggesting that mTORC1 activity is particularly important for leukemia differentiation and proliferation 43–45 . The miRDB is often used to identify candidates of specific miRNA‐target genes.…”

Section: Discussionmentioning

confidence: 99%

A gain‐of‐function mutation in microRNA 142 is sufficient to cause the development of T‐cell leukemia in mice

et al. 2023

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MicroRNAs (miRNAs) play a crucial role in regulating gene expression. MicroRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there have been no reports of carcinogenic point mutations in miRNAs. MicroRNA 142 (miR-142) is frequently mutated in patients with follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). To understand the role of miR-142 mutation in blood cancers, the CRISPR-Cas9 system was utilized to successfully generate miR-142-55A>G mutant knock-in (Ki) mice, simulating the most frequent mutation in patients with miR-142 mutated AML/MDS. Bone marrow cells from miR-142 mutant heterozygous Ki mice were transplanted, and we found that the miR-142 mutant/wild-type cells were sufficient for the development of CD8 + Tcell leukemia in mice post-transplantation. RNA-sequencing analysis in hematopoietic stem/progenitor cells and CD8 + T-cells revealed that miR-142-Ki/+ cells had increased expression of the mTORC1 activator, a potential target of wild-type miR-142-3p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt-mTOR pathway was suppressed in miR-142-55A>G heterozygous cells, indicating that these genes are repressed by the mutant miR-142-3p. Thus, in addition to the loss of function due to the halving of wild-type miR-142-3p alleles, mutated miR-142-3p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.

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“…Interestingly both IL-7R and the downstream mediator JAK1 were identi ed to be preferentially lost in the presence of Notch inhibition. Furthermore, we focused on CyclinD3 which has been demonstrated to be essential for T-ALL induction (32) in a murine model and CDK6, recently identi ed as molecular target in T-ALL (33).…”

Section: Discussionmentioning

confidence: 99%

Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia

Radtke

Cao²,

Buendía

et al. 2023

Preprint

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Gain-of-function mutations in NOTCH1 are among the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL), making the Notch signaling pathway a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss of Phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1) causes resistance to Notch inhibition. PIK3R1 deficiency leads to increased PI3K/AKT signaling which regulates the cell cycle and spliceosome machinery, both at the transcriptional and post-translational level. Moreover, several therapeutic combinations have been identified, where simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models.

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Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma

Cited by 28 publications

References 41 publications

Reprogramming of lactate metabolism is linked to the oncogenesis of the virus-induced leukemia

Reprogramming of lactate metabolism is linked to the oncogenesis of the virus-induced leukemia

A gain‐of‐function mutation in microRNA 142 is sufficient to cause the development of T‐cell leukemia in mice

Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia

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