Impaired Condensin Complex and Aurora B kinase underlie mitotic and chromosomal defects in hyperdiploid B-cell ALL

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, and high-hyperdiploidy (HyperD) identifies the most common subtype of pediatric B-ALL. Despite HyperD is an initiating oncogenic event affiliated to childhood B-ALL, the mitotic and chromosomal defects associated to HyperD B-ALL (HyperD-ALL) remain poorly characterized. Here, we have used 54 primary pediatric B-ALL samples to characterize the cellular-molecular mechanisms underlying the mitotic/chromosome defects predicated to be early pathogenic contributors in HyperD-ALL. We report that HyperD-ALL blasts are low proliferative and show a delay in early mitosis at prometaphase, associated to chromosome alignment defects at the metaphase plate leading to robust chromosome segregation defects and non-modal karyotypes. Mechanistically, biochemical, functional and mass-spectrometry assays revealed that condensin complex is impaired in HyperD-ALL cells, leading to chromosome hypocondensation, loss of centromere stiffness and mis-localization of the chromosome passenger complex proteins Aurora B Kinase (AURKB) and Survivin in early mitosis. HyperD-ALL cells show chromatid cohesion defects and impaired spindle assembly checkpoint (SAC) thus undergoing mitotic slippage due to defective AURKB and impaired SAC activity, downstream of condensin complex defects. Chromosome structure/condensation defects and hyperdiploidy were reproduced in healthy CD34+ stem/progenitor cells upon inhibition of AURKB and/or SAC. Collectively, hyperdiploid B-ALL is associated to defective condensin complex, AURKB and SAC.

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Non-Coding RNA Signatures of B-Cell Acute Lymphoblastic Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms22052683 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2683

Author(s):

Princess D. Rodriguez ◽

Hana Paculova ◽

Sophie Kogut ◽

Jessica Heath ◽

Hilde Schjerven ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Molecular Mechanisms ◽

Lymphoblastic Leukemia ◽

Transcriptome Profiling ◽

Rna Seq ◽

Protein Coding ◽

Non Coding Rna ◽

Technological Developments ◽

Cell Acute Lymphoblastic Leukemia

Non-coding RNAs (ncRNAs) comprise a diverse class of non-protein coding transcripts that regulate critical cellular processes associated with cancer. Advances in RNA-sequencing (RNA-Seq) have led to the characterization of non-coding RNA expression across different types of human cancers. Through comprehensive RNA-Seq profiling, a growing number of studies demonstrate that ncRNAs, including long non-coding RNA (lncRNAs) and microRNAs (miRNA), play central roles in progenitor B-cell acute lymphoblastic leukemia (B-ALL) pathogenesis. Furthermore, due to their central roles in cellular homeostasis and their potential as biomarkers, the study of ncRNAs continues to provide new insight into the molecular mechanisms of B-ALL. This article reviews the ncRNA signatures reported for all B-ALL subtypes, focusing on technological developments in transcriptome profiling and recently discovered examples of ncRNAs with biologic and therapeutic relevance in B-ALL.

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Anlotinib Shows Potent Antileukemia Effects in B-Cell Acute Lymphocytic Leukemia through the Blockage of Angiogenic Related Pathways

Blood ◽

10.1182/blood-2020-141039 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-49

Author(s):

Qiuling Chen ◽

Yuelong Jiang ◽

Qinwei Chen ◽

Long Liu ◽

Bing Xu

Keyword(s):

B Cell ◽

Solid Tumors ◽

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Unmet Need ◽

Lymphocytic Leukemia ◽

Advanced Lung Cancer ◽

Antitumor Effects

Acute lymphoblastic leukemia (ALL) derives from the malignant transformation of lymphoid progenitor cells with ~85% being originated from B-cell progenitors (B-ALL). Despite fairly good prognoses for most pediatric B-ALL patients, the outcome is fatal in over 50% of adult patients who have a recurrent or progressive disease and lack of effective therapeutic approaches. Therefore, novel treatment strategies with high efficacy and low toxicity are an unmet need for B-ALL patients, especially those with relapsed or refractory status. Angiogenesis is a process of new vessel formation that requires the participation of multiple proangiogenic factors (e.g., VEGF, PDGF, and FGF) and their corresponding receptors (e.g., VEGFR, PDGFR, and FGFR). Angiogenesis, a well-established feature of solid tumors, also contributes to leukemia progression and correlates with the involvement of specific sanctuary sites in ALL, highlighting that the perturbation of angiogenesis would be an attractive approach for ALL treatment. Anlotinib is an oral tyrosine kinase (TKI) inhibitor with a broad range of antitumor effects via the suppression of VEGFR, PDGFR and FGFR. Of importance, anlotinib has been approved for the treatment of advanced lung cancer in China. Here, we evaluated the antileukemia activity of anlotinib in preclinical B-ALL models and its underlying molecular mechanisms. In this study, we observed that anlotinib significantly blunted the capability of cell proliferation and arrested cell cycle at G2 phase in B-ALL cell lines. Subsequently, we found that anlotinib resulted in remarkably enhanced apoptosis in B-ALL in vitro. To assess the in vivo antileukemia potential, we established a B-ALL patient-derived xenograft (PDX) mouse model and then treated the B-ALL PDX model with anlotinib. As a result, oral administration of anlotinib pronouncedly delayed in vivo B-ALL cell growth and reduced leukemia burden with acceptable safety profiles in this model. As for the mechanism of action, the antileukemia effect of anlotinib was associated with the disruption of the role of VEGFR2, PDGFRb, and FGFR3. Moreover, we revealed that this drug blocked the PI3K/AKT/mTOR/ signaling, a pathway that is linked with angiogenesis and its proangiogenic regulators, including VEGFR2, PDGFRb, and FGFR3. In aggregate, these results indicate that anlotinib is a potent antitumor agent for the treatment of B-ALL via the inhibition of angiogenic relevant pathways, which provide a novel potential treatment intervention for patients with B-ALL who have little effective therapy options. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Anlotinib originally designed by China is a novel orally active multitarget inhibitor that is evaluating in clinical trials against multiple solid tumors.

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The right place at the right time: Aurora B kinase localization to centromeres and kinetochores

Essays in Biochemistry ◽

10.1042/ebc20190081 ◽

2020 ◽

Vol 64 (2) ◽

pp. 299-311 ◽

Cited By ~ 2

Author(s):

Amanda J. Broad ◽

Jennifer G. DeLuca

Keyword(s):

Spindle Assembly Checkpoint ◽

Protein Complexes ◽

Centromeric Heterochromatin ◽

Aurora B ◽

Mitotic Chromosomes ◽

Large Protein ◽

Aurora B Kinase ◽

Centromeric Protein ◽

Spindle Microtubules ◽

The Right

Abstract The fidelity of chromosome segregation during mitosis is intimately linked to the function of kinetochores, which are large protein complexes assembled at sites of centromeric heterochromatin on mitotic chromosomes. These key “orchestrators” of mitosis physically connect chromosomes to spindle microtubules and transduce forces through these connections to congress chromosomes and silence the spindle assembly checkpoint. Kinetochore-microtubule attachments are highly regulated to ensure that incorrect attachments are not prematurely stabilized, but instead released and corrected. The kinase activity of the centromeric protein Aurora B is required for kinetochore-microtubule destabilization during mitosis, but how the kinase acts on outer kinetochore substrates to selectively destabilize immature and erroneous attachments remains debated. Here, we review recent literature that sheds light on how Aurora B kinase is recruited to both centromeres and kinetochores and discuss possible mechanisms for how kinase interactions with substrates at distinct regions of mitotic chromosomes are regulated.

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KCTD15 is overexpressed in human childhood B-cell acute lymphoid leukemia

Scientific Reports ◽

10.1038/s41598-019-56701-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Giovanni Smaldone ◽

Giuliana Beneduce ◽

Mariarosaria Incoronato ◽

Katia Pane ◽

Monica Franzese ◽

...

Keyword(s):

B Cell ◽

Molecular Mechanisms ◽

Childhood Leukemia ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Pokeweed Mitogen ◽

Pathological State ◽

Lymphoid Leukemia ◽

Continuous Cell Lines ◽

Tetramerization Domain

AbstractLeukemic cells originate from the malignant transformation of undifferentiated myeloid/lymphoid hematopoietic progenitors normally residing in bone marrow. As the precise molecular mechanisms underlying this heterogeneous disease are yet to be disclosed, the identification and the validation of novel actors in leukemia is of extreme importance. Here, we show that KCTD15, a member of the emerging class of KCTD ((K)potassium Channel Tetramerization Domain containing) proteins, is strongly upregulated in patients affected by B-cell type acute lymphoblastic leukemia (B-ALL) and in continuous cell lines (RS4;11, REH, TOM-1, SEM) derived from this form of childhood leukemia. Interestingly, KCTD15 downregulation induces apoptosis and cell death suggesting that it has a role in cellular homeostasis and proliferation. In addition, stimulation of normal lymphocytes with the pokeweed mitogen leads to increased KCTD15 levels in a fashion comparable to those observed in proliferating leukemic cells. In this way, the role of KCTD15 is likely not confined to the B-ALL pathological state and extends to activation and proliferation of normal lymphocytes. Collectively, data here presented indicate that KCTD15 is an important and hitherto unidentified player in childhood lymphoid leukemia, and its study could open a new scenario for the identification of altered and still unknown molecular pathways in leukemia.

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Modeling Dose and Schedule Effects of AZD2811 Nanoparticles Targeting Aurora B Kinase for Treatment of Diffuse Large B-cell Lymphoma

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-18-0577 ◽

2019 ◽

Vol 18 (5) ◽

pp. 909-919 ◽

Cited By ~ 2

Author(s):

Nicolas Floc'h ◽

Susan Ashton ◽

Douglas Ferguson ◽

Paula Taylor ◽

Larissa S. Carnevalli ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Aurora B ◽

Aurora B Kinase ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Schedule Effects

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Centromere-localized Aurora B kinase is required for the fidelity of chromosome segregation

The Journal of Cell Biology ◽

10.1083/jcb.201907092 ◽

2019 ◽

Vol 219 (2) ◽

Cited By ~ 9

Author(s):

Cai Liang ◽

Zhenlei Zhang ◽

Qinfu Chen ◽

Haiyan Yan ◽

Miao Zhang ◽

...

Keyword(s):

Chromosome Segregation ◽

Essential Role ◽

Spindle Assembly Checkpoint ◽

Histone H3 ◽

Spindle Assembly ◽

Aurora B ◽

Aurora B Kinase ◽

Chromosome Missegregation ◽

Proper Timing ◽

Segregation Of Chromosomes

Aurora B kinase plays an essential role in chromosome bi-orientation, which is a prerequisite for equal segregation of chromosomes during mitosis. However, it remains largely unclear whether centromere-localized Aurora B is required for faithful chromosome segregation. Here we show that histone H3 Thr-3 phosphorylation (H3pT3) and H2A Thr-120 phosphorylation (H2ApT120) can independently recruit Aurora B. Disrupting H3pT3-mediated localization of Aurora B at the inner centromere impedes the decline in H2ApT120 during metaphase and causes H2ApT120-dependent accumulation of Aurora B at the kinetochore-proximal centromere. Consequently, silencing of the spindle assembly checkpoint (SAC) is delayed, whereas the fidelity of chromosome segregation is negligibly affected. Further eliminating an H2ApT120-dependent pool of Aurora B restores proper timing for SAC silencing but increases chromosome missegregation. Our data indicate that H2ApT120-mediated localization of Aurora B compensates for the loss of an H3pT3-dependent pool of Aurora B to correct improper kinetochore–microtubule attachments. This study provides important insights into how centromeric Aurora B regulates SAC and kinetochore attachment to microtubules to ensure error-free chromosome segregation.

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Interplay between mitotic kinesins and the Aurora kinase–PP1 (protein phosphatase 1) axis

Biochemical Society Transactions ◽

10.1042/bst20130191 ◽

2013 ◽

Vol 41 (6) ◽

pp. 1761-1765 ◽

Cited By ~ 11

Author(s):

John C. Meadows

Keyword(s):

Protein Phosphatase ◽

Spindle Assembly Checkpoint ◽

Spindle Checkpoint ◽

Aurora Kinase ◽

Protein Phosphatase 1 ◽

Aurora B ◽

Spatial Gradient ◽

Cell Cycle Regulators ◽

Aurora B Kinase ◽

Surveillance Mechanism

Correct transmission of genetic information from mother to daughter cells is necessary for development and survival. Accurate segregation is achieved by bipolar attachment of sister kinetochores in each chromatid pair to spindle microtubules emanating from opposite spindle poles, a process known as chromosome bi-orientation. Achieving this requires dynamic interplay between kinetochore proteins, kinesin motor proteins and cell cycle regulators. Chromosome bi-orientation is monitored by a surveillance mechanism known as the SAC (spindle assembly checkpoint). The Aurora B kinase, which is bound to the inner centromere during early mitosis, plays a central role in both chromosome bi-orientation and the spindle checkpoint. The application of tension across centromeres establishes a spatial gradient of high phosphorylation activity at the inner centromere and low phosphorylation activity at the outer kinetochore. This gradient is further refined by the association of PP1 (protein phosphatase 1) to the outer kinetochore, which stabilizes kinetochore–microtubule interactions and silences the spindle checkpoint by dephosphorylating Aurora B kinase targets when chromosome bi-orientation is achieved. In the present review, I discuss emerging evidence that bidirectional cross-talk between mitotic kinesins and the Aurora kinase–PP1 axis is crucial for co-ordinating chromosome bi-orientation and spindle checkpoint signalling in eukaryotes.

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Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis

Blood ◽

10.1182/blood-2003-11-3857 ◽

2004 ◽

Vol 103 (12) ◽

pp. 4602-4609 ◽

Cited By ~ 31

Author(s):

Aihong Li ◽

Montse Rue ◽

Jianbiao Zhou ◽

Hongjun Wang ◽

Meredith A. Goldwasser ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Heavy Chain ◽

Molecular Mechanisms ◽

Lymphoblastic Leukemia ◽

Tumor Biology ◽

Vdj Recombination ◽

Childhood All ◽

Increased Risk ◽

B Lineage

Abstract Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated preferential usage of specific variable (V), diversity (D), and joining (J) genes at different stages of B-cell development and in B-cell malignancies, and this has provided insight into B-cell maturation and selection. Knowledge of the association between rearrangement patterns based on updated databases and clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is limited. We analyzed 381 IgH sequences identified at presentation in 317 children with B-lineage ALL and assessed the VHDHJH gene utilization profiles. The DHJH-proximal VH segments and the DH2 gene family were significantly overrepresented. Only 21% of VH-JH joinings were potentially productive, a finding associated with a trend toward an increased risk of relapse. These results suggest that physical location at the VH locus is involved in preferential usage of DHJH-proximal VH segments whereas DH and JH segment usage is governed by position-independent molecular mechanisms. Molecular pathophysiology appears relevant to clinical outcome in patients who have only productive rearrangements, and specific rearrangement patterns are associated with differences in the tumor biology of childhood ALL. (Blood. 2004;103:4602-4609)

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Enrichment of Aurora B kinase at the inner kinetochore controls outer kinetochore assembly

The Journal of Cell Biology ◽

10.1083/jcb.201901004 ◽

2019 ◽

Vol 218 (10) ◽

pp. 3237-3257 ◽

Cited By ~ 10

Author(s):

Mary Kate Bonner ◽

Julian Haase ◽

Jason Swinderman ◽

Hyunmi Halas ◽

Lisa M. Miller Jenkins ◽

...

Keyword(s):

Xenopus Laevis ◽

Central Region ◽

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Aurora B ◽

Aurora B Kinase ◽

Kinetochore Assembly ◽

Egg Extracts ◽

Chromosome Attachment

Outer kinetochore assembly enables chromosome attachment to microtubules and spindle assembly checkpoint (SAC) signaling in mitosis. Aurora B kinase controls kinetochore assembly by phosphorylating the Mis12 complex (Mis12C) subunit Dsn1. Current models propose Dsn1 phosphorylation relieves autoinhibition, allowing Mis12C binding to inner kinetochore component CENP-C. Using Xenopus laevis egg extracts and biochemical reconstitution, we found that autoinhibition of the Mis12C by Dsn1 impedes its phosphorylation by Aurora B. Our data indicate that the INCENP central region increases Dsn1 phosphorylation by enriching Aurora B at inner kinetochores, close to CENP-C. Furthermore, centromere-bound CENP-C does not exchange in mitosis, and CENP-C binding to the Mis12C dramatically increases Dsn1 phosphorylation by Aurora B. We propose that the coincidence of Aurora B and CENP-C at inner kinetochores ensures the fidelity of kinetochore assembly. We also found that the central region is required for the SAC beyond its role in kinetochore assembly, suggesting that kinetochore enrichment of Aurora B promotes the phosphorylation of other kinetochore substrates.

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