Prognostic importance of Aurora Kinases and mitotic spindle genes transcript levels in Myelodysplastic syndrome

Borges, Daniela de Paula; Santos, Antônio Wesley Araújo Dos; Paier, Carlos Roberto Koscky; Júnior, Howard Lopes Ribeiro; Costa, Marcos Benedito Caldas; Farias, Izabelle Rocha; Oliveira, Roberta Taiane Germano de; França, Ivo Gabriel da Frota; Cavalcante, Gabrielle; Magalhães, Sílvia Maria Meira; Pinheiro, Ronald Feitosa

doi:10.1016/j.leukres.2017.11.013

Cited by 17 publications

(8 citation statements)

References 50 publications

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“…Future research is warranted to test whether other components of the mitotic spindle or spindle assembly checkpoint are conditionally required in BRCA2-defective cells. In this context, especially MAD2 and CDC20 are interesting, as their expression is highly correlated to TPX2 levels [39].…”

Section: Discussionmentioning

confidence: 99%

TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells

et al. 2018

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Genomic instability is a hallmark feature of cancer cells, and can be caused by defective DNA repair, for instance due to inactivation of BRCA2. Paradoxically, loss of Brca2 in mice results in embryonic lethality, whereas cancer cells can tolerate BRCA2 loss. This holds true for multiple DNA repair genes, and suggests that cancer cells are molecularly "rewired" to cope with defective DNA repair and the resulting high levels of genomic instability. In this study, we aim to identify genes that genomically unstable cancer cells rely on for their survival. Using functional genomic mRNA (FGmRNA) profiling, 16,172 cancer samples were previously ranked based on their degree of genomic instability. We analyzed the top 250 genes that showed a positive correlation between FGmRNA levels and the degree of genomic instability, in a co-functionality network. Within this co-functionality network, a strong cluster of 11 cell cycle-related genes was identified, including TPX2. We then assessed the dependency on these 11 genes in the context of survival of genomically unstable cancer cells, induced by BRCA2 inactivation. Depletion of TPX2 or its associated kinase Aurora-A preferentially reduced cell viability in a panel of BRCA2-deficient cancer cells. In line with these findings, BRCA2-depleted and BRCA2-mutant human cell lines, or tumor cell lines derived from Brca2;p53 mice showed increased sensitivity to the Aurora-A kinase inhibitor alisertib, with delayed mitotic progression and frequent mitotic failure. Our findings reveal that BRCA2-deficient cancer cells show enhanced sensitivity to inactivation of TPX2 or its partner Aurora-A, which points at an actionable dependency of genomically unstable cancers.

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Section: Discussionmentioning

confidence: 99%

TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells

et al. 2018

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“…Combination of proTAME with Apcin, doxorubicin and venetoclax show synergic effects. [ 124 , 125 ] MDS CDC20 over-expression in high-risk patients Shorter RFS and inferior OS [ 126 – 128 ] MM CDC20 over-expression in cell lines and high-risk patients Inferior OS proTAME treatment induced G2/M arrest and increased apoptosis. Combination with etoposide and doxorubicin, vincristine or melphalan potentiated proTAME effect.…”

Section: Main Textmentioning

confidence: 99%

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

Bruno

Rorà

Napolitano

et al. 2022

J Exp Clin Cancer Res

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Cell division cycle 20 homologue (CDC20) is a well-known regulator of cell cycle, as it controls the correct segregation of chromosomes during mitosis. Many studies have focused on the biological role of CDC20 in cancer development, as alterations of its functionality have been linked to genomic instability and evidence demonstrated that high CDC20 expression levels are associated with poor overall survival in solid cancers. More recently, novel CDC20 functions have been demonstrated or suggested, including the regulation of apoptosis and stemness properties and a correlation with immune cell infiltration. Here, we here summarize and discuss the role of CDC20 inside and outside mitosis, starting from its network of interacting proteins. In the last years, CDC20 has also attracted more interest in the blood cancer field, being overexpressed and showing an association with prognosis both in myeloid and lymphoid malignancies. Preclinical findings showed that selective CDC20 and APC/CCDC20/APC/CCDH1 inhibitors, namely Apcin and proTAME, are effective against lymphoma and multiple myeloma cells, resulting in mitotic arrest and apoptosis and synergizing with clinically-relevant drugs. The evidence and hypothesis presented in this review provide the input for further biological and chemical studies aiming to dissect novel potential CDC20 roles and targeting strategies in hematological malignancies.

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“…While somatic mutations of genes encoding SAC proteins are reported infrequently, they occur at a nearly 4-fold increased frequency in FA pathway deficient cancers compared to FA pathway proficient cancers (Figure 7). Additionally, disruption of SAC protein function is widely reported in a variety of cancers and nonmutational alterations in SAC proteins, including MAD2, have specifically been reported in AML/MDS (11,16,17,(56)(57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

et al. 2021

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Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo, the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2. Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/-mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC-deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo, show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.

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Prognostic importance of Aurora Kinases and mitotic spindle genes transcript levels in Myelodysplastic syndrome

Cited by 17 publications

References 50 publications

TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells

TPX2/Aurora kinase A signaling as a potential therapeutic target in genomically unstable cancer cells

CDC20 in and out of mitosis: a prognostic factor and therapeutic target in hematological malignancies

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

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