bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2021–12–26
sixteen papers selected by
Valentina Piano, Max Planck Institute of Molecular Physiology
  1. Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase.
  2. Inhibitors of the Bub1 spindle assembly checkpoint kinase: synthesis of BAY-320 and comparison with 2OH-BNPP1.
  3. The Abscission Checkpoint: A Guardian of Chromosomal Stability.
  4. Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis.
  5. VTT-006, an anti-mitotic compound, binds to the Ndc80 complex and suppresses cancer cell growth in vitro.
  6. Protein phosphatase 2A-dependent mitotic hnRNPA1 dephosphorylation and TERRA formation facilitate telomere capping.
  7. Heat shock factor 1 suppression induces spindle abnormalities and sensitizes cells to antimitotic drugs.
  8. Force by minus-end motors Dhc1 and Klp2 collapses the S. pombe spindle following laser ablation.
  9. Coupling DNA Replication and Spindle Function in Saccharomyces cerevisiae.
  10. Mechanisms of influence of the microtubule over-stabilizing ligands on the structure and intrinsic dynamics of α,β-Tubulin.
  11. Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling.
  12. Male triploid oysters of Crassostrea gigas exhibit defects in mitosis and meiosis during early spermatogenesis.
  13. Small-molecule degraders of cyclin-dependent kinase protein: a review.
  14. Transcriptional cyclin-dependent kinases: Potential drug targets in cancer therapy.
  15. Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic Leukemia.
  16. Expression of SnoRNA U50A Is Associated with Better Prognosis and Prolonged Mitosis in Breast Cancer.
  1. Dev Cell. 2021 Dec 20. pii: S1534-5807(21)00948-5. [Epub ahead of print]56(24): 3405
    Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase.
    Onur Sen, Jonathan U Harrison, Nigel J Burroughs, Andrew D McAinsh.
      
    DOI:  https://doi.org/10.1016/j.devcel.2021.11.023
  2. R Soc Open Sci. 2021 Dec;8(12): 210854
    Inhibitors of the Bub1 spindle assembly checkpoint kinase: synthesis of BAY-320 and comparison with 2OH-BNPP1.
    Ilma Amalina, Ailsa Bennett, Helen Whalley, David Perera, Joanne C McGrail, Anthony Tighe, David J Procter, Stephen S Taylor.
      Bub1 is a serine/threonine kinase proposed to function centrally in mitotic chromosome alignment and the spindle assembly checkpoint (SAC); however, its role remains controversial. Although it is well documented that Bub1 phosphorylation of Histone 2A at T120 (H2ApT120) recruits Sgo1/2 to kinetochores, the requirement of its kinase activity for chromosome alignment and the SAC is debated. As small-molecule inhibitors are invaluable tools for investigating kinase function, we evaluated two potential Bub1 inhibitors: 2OH-BNPPI and BAY-320. After confirming that both inhibit Bub1 in vitro, we developed a cell-based assay for Bub1 inhibition. We overexpressed a fusion of Histone 2B and Bub1 kinase region, tethering it in proximity to H2A to generate a strong ectopic H2ApT120 signal along chromosome arms. Ectopic signal was effectively inhibited by BAY-320, but not 2OH-BNPP1 at concentrations tested. In addition, only BAY-320 was able to inhibit endogenous Bub1-mediated Sgo1 localization. Preliminary experiments using BAY-320 suggest a minor role for Bub1 kinase activity in chromosome alignment and the SAC; however, BAY-320 may exhibit off-target effects at the concentration required. Thus, 2OH-BNPP1 may not be an effective Bub1 inhibitor in cellulo, and while BAY-320 can inhibit Bub1 in cells, off-target effects highlight the need for improved Bub1 inhibitors.
    Keywords:  2OH-BNPP1; BAY-320; Bub1; kinase inhibitor; spindle assembly checkpoint
    DOI:  https://doi.org/10.1098/rsos.210854
  3. Cells. 2021 Nov 29. pii: 3350. [Epub ahead of print]10(12):
    The Abscission Checkpoint: A Guardian of Chromosomal Stability.
    Eleni Petsalaki, George Zachos.
      The abscission checkpoint contributes to the fidelity of chromosome segregation by delaying completion of cytokinesis (abscission) when there is chromatin lagging in the intercellular bridge between dividing cells. Although additional triggers of an abscission checkpoint-delay have been described, including nuclear pore defects, replication stress or high intercellular bridge tension, this review will focus only on chromatin bridges. In the presence of such abnormal chromosomal tethers in mammalian cells, the abscission checkpoint requires proper localization and optimal kinase activity of the Chromosomal Passenger Complex (CPC)-catalytic subunit Aurora B at the midbody and culminates in the inhibition of Endosomal Sorting Complex Required for Transport-III (ESCRT-III) components at the abscission site to delay the final cut. Furthermore, cells with an active checkpoint stabilize the narrow cytoplasmic canal that connects the two daughter cells until the chromatin bridges are resolved. Unsuccessful resolution of chromatin bridges in checkpoint-deficient cells or in cells with unstable intercellular canals can lead to chromatin bridge breakage or tetraploidization by regression of the cleavage furrow. In turn, these outcomes can lead to accumulation of DNA damage, chromothripsis, generation of hypermutation clusters and chromosomal instability, which are associated with cancer formation or progression. Recently, many important questions regarding the mechanisms of the abscission checkpoint have been investigated, such as how the presence of chromatin bridges is signaled to the CPC, how Aurora B localization and kinase activity is regulated in late midbodies, the signaling pathways by which Aurora B implements the abscission delay, and how the actin cytoskeleton is remodeled to stabilize intercellular canals with DNA bridges. Here, we review recent progress toward understanding the mechanisms of the abscission checkpoint and its role in guarding genome integrity at the chromosome level, and consider its potential implications for cancer therapy.
    Keywords:  ATM; Aurora B; CPC; Chk2; Chmp4c; DNA damage; ESCRT; abscission checkpoint; actin patches; cancer; chromatin bridges; chromosomal instability; cytokinesis; midbody
    DOI:  https://doi.org/10.3390/cells10123350
  4. Development. 2021 Dec 15. pii: dev199800. [Epub ahead of print]148(24):
    Maternal Smc3 protects the integrity of the zygotic genome through DNA replication and mitosis.
    Wei-Ting Yueh, Vijay Pratap Singh, Jennifer L Gerton.
      Aneuploidy is frequently observed in oocytes and early embryos, begging the question of how genome integrity is monitored and preserved during this crucial period. SMC3 is a subunit of the cohesin complex that supports genome integrity, but its role in maintaining the genome during this window of mammalian development is unknown. We discovered that, although depletion of Smc3 following meiotic S phase in mouse oocytes allowed accurate meiotic chromosome segregation, adult females were infertile. We provide evidence that DNA lesions accumulated following S phase in SMC3-deficient zygotes, followed by mitosis with lagging chromosomes, elongated spindles, micronuclei, and arrest at the two-cell stage. Remarkably, although centromeric cohesion was defective, the dosage of SMC3 was sufficient to enable embryogenesis in juvenile mutant females. Our findings suggest that, despite previous reports of aneuploidy in early embryos, chromosome missegregation in zygotes halts embryogenesis at the two-cell stage. Smc3 is a maternal gene with essential functions in the repair of spontaneous damage associated with DNA replication and subsequent chromosome segregation in zygotes, making cohesin a key protector of the zygotic genome.
    Keywords:  Chromosome segregation; Cohesin; Developmental competence; Juvenile; Maternal-effect gene; Micronuclei; Mouse; SMC3; Spontaneous DNA damage; Zygote
    DOI:  https://doi.org/10.1242/dev.199800
  5. Oncoscience. 2021 ;8 134-153
    VTT-006, an anti-mitotic compound, binds to the Ndc80 complex and suppresses cancer cell growth in vitro.
    Leena J Laine, Jenni H E Mäki-Jouppila, Emma Kutvonen, Pekka Tiikkainen, Thomas K M Nyholm, Jerry F Tien, Neil T Umbreit, Ville Härmä, Lila Kallio, Trisha N Davis, Charles L Asbury, Antti Poso, Gary J Gorbsky, Marko J Kallio.
      Hec1 (Highly expressed in cancer 1) resides in the outer kinetochore where it works to facilitate proper kinetochore-microtubule interactions during mitosis. Hec1 is overexpressed in various cancers and its expression shows correlation with high tumour grade and poor patient prognosis. Chemical perturbation of Hec1 is anticipated to impair kinetochore-microtubule binding, activate the spindle assembly checkpoint (spindle checkpoint) and thereby suppress cell proliferation. In this study, we performed high-throughput screen to identify novel small molecules that target the Hec1 calponin homology domain (CHD), which is needed for normal microtubule attachments. 4 million compounds were first virtually fitted against the CHD, and the best hit molecules were evaluated in vitro. These approaches led to the identification of VTT-006, a 1,2-disubstituted-tetrahydro-beta-carboline derivative, which showed binding to recombinant Ndc80 complex and modulated Hec1 association with microtubules in vitro. VTT-006 treatment resulted in chromosome congression defects, reduced chromosome oscillations and induced loss of inter-kinetochore tension. Cells remained arrested in mitosis with an active spindle checkpoint for several hours before undergoing cell death. VTT-006 suppressed the growth of several cancer cell lines and enhanced the sensitivity of HeLa cells to Taxol. Our findings propose that VTT-006 is a potential anti-mitotic compound that disrupts M phase, impairs kinetochore-microtubule interactions, and activates the spindle checkpoint.
    Keywords:  Hec1; Ndc80; cell division; mitosis; spindle assembly checkpoint
    DOI:  https://doi.org/10.18632/oncoscience.549
  6. Mol Cancer Res. 2021 Dec 21. pii: molcanres.MCR-21-0581-E.2021. [Epub ahead of print]
    Protein phosphatase 2A-dependent mitotic hnRNPA1 dephosphorylation and TERRA formation facilitate telomere capping.
    Jiang-Dong Sui, Zheng Tang, Benjamin P C Chen, Ping Huang, Meng-Qi Yang, Nuo-Han Wang, Hao-Nan Yang, Hong-Lei Tu, Qing-Ming Jiang, Jing Zhang, Ying Wang, Yong-Zhong Wu.
      The heterogeneous nuclear ribonucleoprotein A1(hnRNPA1), telomeric repeat-containing RNA (TERRA), and protection of telomeres 1 (POT1) have been reported to orchestrate to displace replication protein A (RPA) from telomeric overhangs, ensuring orderly telomere replication and capping. Our previous studies further demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-dependent hnRNPA1 phosphorylation plays a crucial role in the promotion of hnRNPA1 binding to telomeric overhangs and RPA displacement during G2/M phases. However, it is unclear that how the subsequent exchange between hnRNPA1 and POT1 is orchestrated. Here we report that the protein phosphatase 2A (PP2A) depends on its scaffold subunit, which is called PPP2R1A, to interact with and dephosphorylate hnRNPA1 in the late M phase. Furthermore, PP2A-mediated hnRNPA1 dephosphorylation and TERRA accumulation act in concert to promote the hnRNPA1-to-POT1 switch on telomeric single-stranded DNA. Consequently, defective PPP2R1A results in ATR-mediated DNA damage response at telomeres as well as induction of fragile telomeres. Combined inhibition of ATR and PP2A induces entry into a catastrophic mitosis and leads to synthetic lethality of tumor cells. In addition, PPP2R1A levels correlate with clinical stages and prognosis of multiple types of cancers. Taken together, our results indicate that PP2A is critical for telomere maintenance. Implications:This study demonstrates that the PP2A-dependent hnRNPA1 dephosphorylation and TERRA accumulation facilitates the formation of the protective capping structure of newly replicated telomeres, thus exerting essential oncogenic role in tumorigenesis.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0581
  7. Cell Div. 2021 Dec 18. 16(1): 8
    Heat shock factor 1 suppression induces spindle abnormalities and sensitizes cells to antimitotic drugs.
    Hsiao-Hui Kuo, Zhi-Rou Su, Jing-Yuan Chuang, Ling-Huei Yih.
       BACKGROUND: Heat shock factor 1 (HSF1) is the master regulator of the heat shock response and supports malignant cell transformation. Recent work has shown that HSF1 can access the promoters of heat shock proteins (HSPs) and allow HSP expression during mitosis. It also acts as a mitotic regulator, controlling chromosome segregation. In this study, we investigated whether the transactivation activity of HSF1 is required for the assembly of mitotic spindles.
    RESULTS: Our results showed that phosphorylation of HSF1 at serine 326 (S326) and its transactivation activity were increased during mitosis. Inhibition of the transactivation activity of HSF1 by KRIBB11 or CCT251263 during mitosis significantly increased the proportion of mitotic cells with abnormal spindles. It also hampered the reassembly of spindle microtubules after nocodazole treatment and washout by impeding the formation of chromosomal microtubule asters. Depletion of HSF1 led to defects in mitotic spindle assembly, subsequently attenuating cell proliferation and anchorage-independent cell growth (AIG). These HSF1 depletion-induced effects could be rescued by ectopically expressing wild-type HSF1 or a constitutively active mutant (∆202-316, caHSF1) but not the S326A or dominant negative (∆361-529, dnHSF1) mutants. In addition, overexpression of HSP70 partially reduced HSF1 depletion-induced spindle abnormalities. These results indicate that HSF1 may support cell proliferation and AIG by maintaining spindle integrity through its transactivation activity. Furthermore, inhibition of HSF1 transactivation activity by KRIBB11 or CCT251236 can enhance diverse anti-mitosis drug-induced spindle defects and cell death.
    CONCLUSIONS: The increased transactivation activity of HSF1 during mitosis appears to be required for accurate assembly of mitotic spindles, thereby supporting cell viability and probably AIG. In addition, inhibition of the transactivation activity of HSF1 may enhance the mitotic errors and cell death induced by anti-mitosis drugs.
    Keywords:  Cell death; HSF1; Spindle assembly
    DOI:  https://doi.org/10.1186/s13008-021-00075-8
  8. Biophys J. 2021 Dec 21. pii: S0006-3495(21)03943-6. [Epub ahead of print]
    Force by minus-end motors Dhc1 and Klp2 collapses the S. pombe spindle following laser ablation.
    Parsa Zareiesfandabadi, Mary Williard Elting.
      A microtubule-based machine called the mitotic spindle segregates chromosomes when eukaryotic cells divide. In the fission yeast S. pombe, which undergoes closed mitosis, the spindle forms a single bundle of microtubules inside the nucleus. During elongation, the spindle extends via antiparallel microtubule sliding by molecular motors. These extensile forces from the spindle are thought to resist compressive forces from the nucleus. We probe the mechanism and maintenance of this force balance via laser ablation of spindles at various stages of mitosis. We find that spindle pole bodies collapse toward each other following ablation, but spindle geometry is often rescued, allowing spindles to resume elongation. While this basic behavior has been previously observed, many questions remain about the phenomenon's dynamics, mechanics, and molecular requirements. In this work, we find that previously hypothesized viscoelastic relaxation of the nucleus cannot explain spindle shortening in response to laser ablation. Instead, spindle collapse requires microtubule dynamics and is powered by the minus-end directed motor proteins dynein Dhc1 and kinesin-14 Klp2, but does not require the minus-end directed kinesin Pkl1.
    DOI:  https://doi.org/10.1016/j.bpj.2021.12.019
  9. Cells. 2021 Nov 30. pii: 3359. [Epub ahead of print]10(12):
    Coupling DNA Replication and Spindle Function in Saccharomyces cerevisiae.
    Dimitris Liakopoulos.
      In the yeast Saccharomyces cerevisiae DNA replication and spindle assembly can overlap. Therefore, signaling mechanisms modulate spindle dynamics in order to ensure correct timing of chromosome segregation relative to genome duplication, especially when replication is incomplete or the DNA becomes damaged. This review focuses on the molecular mechanisms that coordinate DNA replication and spindle dynamics, as well as on the role of spindle-dependent forces in DNA repair. Understanding the coupling between genome duplication and spindle function in yeast cells can provide important insights into similar processes operating in other eukaryotic organisms, including humans.
    Keywords:  S-phase checkpoint; cell cycle; replication; spindle; yeast
    DOI:  https://doi.org/10.3390/cells10123359
  10. Comput Biol Chem. 2021 Dec 08. pii: S1476-9271(21)00187-0. [Epub ahead of print]96 107617
    Mechanisms of influence of the microtubule over-stabilizing ligands on the structure and intrinsic dynamics of α,β-Tubulin.
    Debadrita Basu, Sarmistha Majumdar, Nishita Mandal, Shubhra Ghosh Dastidar.
      The intervention into the cell cycle progression by administering microtubule over-stabilizing ligands that arrest the mitotic cell division by preventing spindle dissociation, is a promising strategy to fight against cancers. The building blocks of the microtubules and the spindles, i.e. the α,β-tubulin dimer, upon binding of such ligands, stay more comfortably in the microtubular multimeric form; the phenomenon of which is the key to the said over-stabilization. Using two such over-stabilizing ligands, Taxol and Taxotere, the present work reports the collective changes that these ligands induce on the structure and dynamics of the α,β-tubulin dimer which could be reconciled as the molecular basis of the over-stabilization of the microtubules; the trends have been found to be statistically significant across all independent calculations on them. The ligand binding increases the coherence between the residue communities of the two opposite faces of the β-subunit, which in a periodic arrangement in microtubule are knwon to form intermolecular contact with each other. This is likely to create an indirect cooperativity between those structural regions and this is a consequence of the reshuffling of the internal network of interactions upon ligand binding. Such reorganizations are also complemented by the increased contributions of the softer modes of the intrinsic dynamics more, which is likely to increase the plasticity of the system favourable for making structural adjustments in a multimer. Further, the ligands are able to compensate the drawback of lacking one phosphate group in protein-GDP interactions compared to the same for protein-GTP and this is in agreement with the hints form the earlier reports. The findings form a mechanistic basis of the enhanced capacity of the α,β-tubulin dimer to get more favourably accommodated into the microtubule superstructure upon binding either of Taxol and Taxotere.
    Keywords:  Cancer; Molecular dynamics; Taxol; Taxotere; α; β-Tubulin
    DOI:  https://doi.org/10.1016/j.compbiolchem.2021.107617
  11. Cells. 2021 Nov 26. pii: 3327. [Epub ahead of print]10(12):
    Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling.
    Zhixiang Wang.
      The cell cycle is the series of events that take place in a cell, which drives it to divide and produce two new daughter cells. The typical cell cycle in eukaryotes is composed of the following phases: G1, S, G2, and M phase. Cell cycle progression is mediated by cyclin-dependent kinases (Cdks) and their regulatory cyclin subunits. However, the driving force of cell cycle progression is growth factor-initiated signaling pathways that control the activity of various Cdk-cyclin complexes. While the mechanism underlying the role of growth factor signaling in G1 phase of cell cycle progression has been largely revealed due to early extensive research, little is known regarding the function and mechanism of growth factor signaling in regulating other phases of the cell cycle, including S, G2, and M phase. In this review, we briefly discuss the process of cell cycle progression through various phases, and we focus on the role of signaling pathways activated by growth factors and their receptor (mostly receptor tyrosine kinases) in regulating cell cycle progression through various phases.
    Keywords:  G1 phase; G2 phase; M phase; PI3K/Akt; Ras/Erk; S phase; cell cycle; growth factors; receptor tyrosine kinases
    DOI:  https://doi.org/10.3390/cells10123327
  12. FEBS Open Bio. 2021 Dec 22.
    Male triploid oysters of Crassostrea gigas exhibit defects in mitosis and meiosis during early spermatogenesis.
    Floriane Maillard, Nicolas Elie, Nadège Villain-Naud, Mélanie Lepoittevin, Anne-Sophie Martinez, Christophe Lelong.
      The Pacific oyster, Crassostrea gigas is a successive irregular hermaphrodite mollusc which has an annual breeding cycle. Oysters are naturally diploid organisms, but triploid oysters have been developed for use in shellfish aquaculture, with the aim of obtaining sterile animals with commercial value. However, studies have shown that some triploid oysters are partially able to undergo gametogenesis, with numerous proliferating cells closed to diploids (3n alpha) or a partial one with an accumulation of locked germ cells (3n beta). The aim of our study therefore was to understand the regulation of spermatogenesis in both groups of triploid oysters (alpha and beta) from the beginning of spermatogenesis, during mitosis and meiosis events. Our results demonstrate that the reduced spermatogenesis in triploids results from a deregulation of the development of the germinal lineage and the establishment of the gonadal tract led by a lower number of tubules. Morphological cellular investigation also revealed an abnormal condensation of germ cell nuclei and the presence of clear patches in the nucleoplasm of triploid cells, which were more pronounced in beta oysters. Furthermore, studies of molecular and cellular regulation showed a downregulation of mitotic spindle checkpoint in beta oysters, resulting in disturbance of chromosomal segregation, notably on Spindle Assembly Checkpoint involved in the binding of microtubules to chromosomes. Taken together, our results suggest that the lower reproductive ability of triploid oysters may be due to cellular and molecular events such as impairment of spermatogenesis and disruptions of mitosis and meiosis, occurring early and at various stages of the gametogenetic cycle.
    Keywords:   Crassostrea gigas ; meiosis; mitosis; oysters; spermatogenesis; triploid
    DOI:  https://doi.org/10.1002/2211-5463.13356
  13. Future Med Chem. 2021 Dec 23.
    Small-molecule degraders of cyclin-dependent kinase protein: a review.
    Bin Yu, Zekun Du, Yuming Zhang, Zhiyu Li, Jinlei Bian.
      Proteolysis-targeting chimeras are a new modality of chemical tools and potential therapeutics involving the induction of protein degradation. Cyclin-dependent kinase (CDK) protein, which is involved in cycles and transcription cycles, participates in regulation of the cell cycle, transcription and splicing. Proteolysis-targeting chimeras targeting CDKs show several advantages over traditional CDK small-molecule inhibitors in potency, selectivity and drug resistance. In addition, the discovery of molecule glues promotes the development of CDK degraders. Herein, the authors describe the existing CDK degraders and focus on the discussion of the structural characteristics and design of these degraders.
    Keywords:  PROTAC degraders; cyclin-dependent kinase inhibitors; glue degraders; protein degradation; ubiquitin-proteasome system
    DOI:  https://doi.org/10.4155/fmc-2021-0154
  14. Eur J Med Chem. 2021 Dec 16. pii: S0223-5234(21)00905-3. [Epub ahead of print]229 114056
    Transcriptional cyclin-dependent kinases: Potential drug targets in cancer therapy.
    Yi Liu, Leilei Fu, Junhao Wu, Ming Liu, Guan Wang, Bo Liu, Lan Zhang.
      In the wake of the development of the concept of cell cycle and its limiting points, cyclin-dependent kinases (CDKs) are considered to play a central role in regulating cell cycle progression. Recent studies have strongly demonstrated that CDKs also has multiple functions, especially in response to extracellular and intracellular signals by interfering with transcriptional events. Consequently, how to inhibit their function has been a hot research topic. It is worth noting that the key role of CDKs in regulating transcription has been explored in recent years, but its related pharmacological targets are less developed, and most inhibitors have not entered the clinical stage. Accordingly, this perspective focus on the biological functions of transcription related CDKs and their complexes, some key upstream and downstream signals, and inhibitors for cancer treatment in recent years. In addition, some corresponding combined treatment strategies will provide a more novel perspective for future cancer remedy.
    Keywords:  Biological function; Cancer therapy; Selective transcriptional CDKs inhibitors; Transcriptional CDKs
    DOI:  https://doi.org/10.1016/j.ejmech.2021.114056
  15. Haematologica. 2021 Dec 23.
    Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic Leukemia.
    Karen L Bride, Hai Hu, Anastasia Tikhonova, Tori J Fuller, Tiffaney L Vincent, Rawan Shraim, Marilyn M Li, William L Carroll, Elizabeth A Raetz, Iannis Aifantis, David T Teachey.
      Despite improvements in outcomes for children with B and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKis) with cytotoxic agents. Based on these observations, we broadened evaluation of two CDKis, palbociclib (PD-0332991, Pfizer) and ribociclib (LEE011, Novartis) in B and T-ALL as single agent and in combination with conventional cytotoxic chemotherapy, using different schedules in preclinical models. As monotherapy, CDKis caused cell cycle arrest with a significant decrease in S phase entry and were active in vivo across a broad number of patient-derived xenograft samples. Prolonged monotherapy induces resistance, for which we identified a potential novel mechanism using transcriptome profiling. Importantly, simultaneous but not sequential treatment of CDKis with conventional chemotherapy (dexamethasone, L-asparaginase and vincristine) led to improved efficacy compared to monotherapy in vivo. We provide novel evidence that combining CDKis and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical trial.
    DOI:  https://doi.org/10.3324/haematol.2021.279410
  16. Cancers (Basel). 2021 Dec 15. pii: 6304. [Epub ahead of print]13(24):
    Expression of SnoRNA U50A Is Associated with Better Prognosis and Prolonged Mitosis in Breast Cancer.
    Jie-Ning Li, Ming-Yang Wang, Yi-Ting Chen, Yao-Lung Kuo, Pai-Sheng Chen.
      Small nucleolar RNAs (snoRNAs) are small noncoding RNAs generally recognized as housekeeping genes. Genomic analysis has shown that snoRNA U50A (U50A) is a candidate tumor suppressor gene deleted in less than 10% of breast cancer patients. To date, the pathological roles of U50A in cancer, including its clinical significance and its regulatory impact at the molecular level, are not well-defined. Here, we quantified the copy number of U50A in human breast cancer tissues. Our results showed that the U50A expression level is correlated with better prognosis in breast cancer patients. Utilizing RNA-sequencing for transcriptomic analysis, we revealed that U50A downregulates mitosis-related genes leading to arrested cancer cell mitosis and suppressed colony-forming ability. Moreover, in support of the impacts of U50A in prolonging mitosis and inhibiting clonogenic activity, breast cancer tissues with higher U50A expression exhibit accumulated mitotic tumor cells. In conclusion, based on the evidence from U50A-downregulated mitosis-related genes, prolonged mitosis, repressed colony-forming ability, and clinical analyses, we demonstrated molecular insights into the pathological impact of snoRNA U50A in human breast cancer.
    Keywords:  breast cancer; cancer prognosis; mitosis; snoRNA
    DOI:  https://doi.org/10.3390/cancers13246304
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