scholarly journals BLNK suppresses pre–B-cell leukemogenesis through inhibition of JAK3

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1483-1492 ◽  
Author(s):  
Joji Nakayama ◽  
Mutsumi Yamamoto ◽  
Katsuhiko Hayashi ◽  
Hitoshi Satoh ◽  
Kenji Bundo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Leukemia Cells ◽  
Cell Leukemia ◽  
Cycle Arrest ◽  
B Cell Leukemia

Abstract Pre–B-cell leukemia spontaneously develops in BLNK-deficient mice, and pre–B-cell acute lymphoblastic leukemia cells in children often lack BLNK protein expression, demonstrating that BLNK functions as a tumor suppressor. However, the mechanism by which BLNK suppresses pre–B-cell leukemia, as well as the identification of other genetic alterations that collaborate with BLNK deficiency to cause leukemogenesis, are still unknown. Here, we demonstrate that the JAK3/STAT5 signaling pathway is constitutively activated in pre-B leukemia cells derived from BLNK−/− mice, mostly due to autocrine production of IL-7. Inhibition of IL-7R signaling or JAK3/STAT5 activity resulted in the induction of p27kip1 expression and cell-cycle arrest, accompanied by apoptosis in the leukemia cells. Transgene-derived constitutively active STAT5 (STAT5b-CA) strongly synergized with the loss of BLNK to initiate leukemia in vivo. In the leukemia cells, exogenously expressed BLNK inhibited autocrine JAK3/STAT5 signaling, resulting in p27kip1 induction, cell-cycle arrest, and apoptosis. BLNK-inhibition of JAK3 was dependent on the binding of BLNK to JAK3. These data indicate that BLNK normally regulates IL-7–dependent proliferation and survival of pre–B cells through direct inhibition of JAK3. Thus, somatic loss of BLNK and concomitant mutations leading to constitutive activation of Jak/STAT5 pathway result in the generation of pre–B-cell leukemia.

scholarly journals Anti-CD19 inhibits the growth of human B-cell tumor lines in vitro and of Daudi cells in SCID mice by inducing cell cycle arrest

Blood ◽  
1994 ◽  
Vol 83 (5) ◽  
pp. 1329-1336 ◽  
Author(s):  
MA Ghetie ◽  
LJ Picker ◽  
JA Richardson ◽  
K Tucker ◽  
JW Uhr ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Inhibitory Effect ◽  
Scid Mice ◽  
Cell Tumor ◽  
Cycle Arrest ◽  
A Chain

Abstract In this report, we extend our previous findings that IgG or F(ab′)2 fragments of HD37 anti-CD19 antibody (Ab) in combination with the immunotoxin (IT), RFB4-anti-CD22-deglycosylated ricin A chain (dgA) (but neither reagent alone), prolonged the survival of SCID mice with disseminated human Daudi lymphoma (SCID/Daudi mice) to 1 year at which time they still remained tumor-free. We explored the mechanisms by which the HD37 Ab exerts antitumor activity in vivo by studying its activity in vitro. We found that it has antiproliferative activity (IC50 = 5.2 - 9.8 x 10(-7) mol/L) on three CD19+ Burkitt's lymphoma cell lines (Daudi, Raji, and Namalwa) but not on a weakly CD19-positive (CD19lo) pre-B cell tumor (Nalm-6). The inhibitory effect was manifested by cell cycle arrest, but not apoptosis. Results using three additional anti-CD19 Abs, suggest that the affinity of the antibody and possibly the epitope which it recognizes may effect its capacity to transmit a signal that induces cell cycle arrest. Hence, therapeutically useful Abs may exert anti-tumor activity by a variety of mechanisms, each of which should be evaluated before undertaking clinical trials in humans.

scholarly journals Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis

2012 ◽  
Vol 36 (3) ◽  
pp. 342-349 ◽  
Author(s):  
Chong Zhang ◽  
Yong-Ku Ryu ◽  
Taylor Z. Chen ◽  
Connor P. Hall ◽  
Daniel R. Webster ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Synergistic Activity ◽  
Cycle Arrest

Epigenetic Control Of Cell Cycle-Promoting Genes By Ikaros and Casein Kinase II In B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3734-3734
Author(s):  
Sinisa Dovat ◽  
Chunhua Song ◽  
Xiaokang Pan ◽  
Yali Ding ◽  
Chandrika S. Gowda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Regulatory Elements ◽  
Preclinical Model ◽  
Cycle Arrest ◽  
Cell Acute Lymphoblastic Leukemia

Abstract IKZF1 (Ikaros) encodes a kruppel-like zinc finger protein that is essential for normal hematopoiesis and acts as a tumor suppressor in acute lymphoblastic leukemia (ALL). The deletion and/or mutation of Ikaros is associated with the development of human T-cell and B-cell acute lymphoblastic leukemia (B-ALL) with poor outcome. In vivo, Ikaros binds DNA and regulates gene expression by chromatin remodeling. Since there is a paucity of known genes that are regulated by Ikaros, the molecular mechanisms through which Ikaros exerts its tumor suppressor function remain unknown. Here we describe studies that identify the targets and mechanisms of Ikaros-mediated epigenetic regulation in human B-ALL. We used chromatin immunoprecipitation coupled with next generation sequencing (ChIP-seq) to identify target genes that are bound by Ikaros in vivo in human B-ALL, and to define epigenetic patterns associated with Ikaros binding. ChIP-seq revealed a large set of Ikaros target genes that contain a characteristic Ikaros binding motif. The largest group of genes that are direct Ikaros targets included genes that are essential for cell cycle progression. These included CDC2, CDC7, CDK2 and CDK6 genes whose deregulation is associated with malignant transformation. The strong binding of ikaros to the promoters of cell cycle-promoting genes was confirmed by quantitative immunoprecipitation in primary leukemia cells. To establish whether Ikaros directly regulates transcription of the cell cycle-promoting genes, their expression was measured in B-ALL cells that were transduced with either a retroviral vector that contains Ikaros, or a control vector. Target gene expression was monitored by qRT-PCR. Ikaros strongly repressed transcription of the cell cycle-promoting genes, which resulted in cell cycle arrest. Global epigenetic profiling using ChIP-seq suggested that Ikaros represses cell cycle-promoting genes by inducing epigenetic changes that are consistent with repressive chromatin. High-resolution epigenetic profiling of the upstream regulatory elements of the cell cycle-promoting genes targeted by Ikaros showed that increased Ikaros expression results in the formation of heterochromatin, which is characterized by the presence of the H3K9me3 histone modification and associated transcriptional repression. Functional analysis revealed that phosphorylation of Ikaros by the oncogenic protein. Casein kinase II (CK2), impairs its function as a transcriptional repressor of the cell cycle-regulating genes. Inhibition of CK2 by specific inhibitors enhances Ikaros-mediated repression of the cell cycle-regulating genes resulting in cessation of cellular proliferation and cell cycle arrest in vitro and in vivo in a B-cell ALL preclinical model. This was associated with increased Ikaros binding and the formation of heterochromatin at upstream regulatory elements of the cell cycle-promoting genes. Our results provide evidence that Ikaros functions as a repressor of cell cycle-promoting genes in B-ALL by directly binding their promoters and inducing the formation of heterochromatin with characteristic H3K9me3 histone modifications Ikaros repressor function is negatively regulated by CK2 kinase in B-cell ALL. Inhibition of CK2 enhances Ikaros mediated-repression of cell cycle-promoting genes resulting in an anti-leukemia effect in a preclinical model of B-cell ALL. Presented data identified the mechanism of action of CK2 inhibitors and demonstrated their efficacy in B-cell ALL preclinical model. Results support the use of CK2 inhibitors in Phase I clinical trial. Supported by National Institutes of Health R01 HL095120 and a St. Baldrick’s Foundation Career Development Award (to S.D.). Disclosures: No relevant conflicts of interest to declare.

A phase I trial of palbociclib in combination with dexamethasone in relapsed or refractory adult B-cell acute lymphoblastic leukemia (ALL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7065-TPS7065 ◽  
Author(s):  
Margaret T. Kasner ◽  
Lindsay Wilde ◽  
Gina Keiffer ◽  
Neil David Palmisiano ◽  
Bruno Calabretta
Keyword(s):  
Cell Cycle ◽  
Phase I ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Maximum Tolerated Dose ◽  
Cyclin D3 ◽  
Cycle Arrest ◽  
Dose Limiting Toxicity

TPS7065 Background: c-Myb is a DNA-binding transcription factor that is highly expressed in immature hematopoietic cells. c-Myb and its products are essential in regulating normal hematopoiesis and influencing leukemogenesis. Knockdown of c-Myb causes cell cycle arrest and apoptosis in pre-B-ALL cells. The effects of c-Myb depend on transcriptional regulation of CDK6 and Bcl-2. c-Myb-silenced Ph+ ALL cells exhibit Rb-dependent cell cycle arrest and apoptosis, both of which are rescued by ectopic expression of cyclin D3, CDK6, and Bcl-2 expression. Preclinical studies suggest that the cytotoxic activity of dexamethasone in ALL cells may be due to decreased c-Myb expression and reduced Bcl-2 levels. Thus, the novel combination of palbociclib, a small molecule CDK4/6 inhibitor, and dexamethasone is a logical approach for the treatment of B-cell ALL. Methods: This is a single arm, phase I, dose escalation study with a traditional 3+3 design. Adult patients with relapsed or refractory B-cell ALL are eligible. Patients with Ph+ ALL must be refractory to or intolerant of standard tyrosine kinase inhibitor therapy. Patients receive a 1-week lead-in of palbociclib alone followed by induction with 4 weeks of palbociclib and dexamethasone. If an adequate response is seen, patients move to maintenance therapy, which consists of 1 week of palbociclib plus dexamethasone followed by 3 weeks of palbociclib alone. Treatment continues until disease progression, dose limiting toxicity, or availability of an alternative therapy. The primary endpoints are dose limiting toxicity and maximum tolerated dose of palbociclib and dexamethasone. Correlative studies, which are performed on pretreatment, day +1 and day +8 samples, include RB phosphorylation and FOXM1 expression as measures of palbociclib activity; CD19+ cell gene expression profiling of (1) p21 expression as an indicator of cell cycle activity, (2) S-Phase, Annexin V/Caspase 3 activation as indicators of proliferation and apoptosis and (3) Myb and Bcl-2 expression as indicators of dexamethasone sensitivity. Cohort 1 is currently enrolling. Once a maximum tolerated dose is established, an expansion cohort is planned. Clinical trial information: NCT03472573.

scholarly journals PIM Inhibitor SMI-4a Induces Cell Apoptosis and Cell Cycle Arrest in B-Cell Acute Lymphocytic Leukemia Cells Via the JAK2/STAT3 Pathway

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4083-4083 ◽  
Author(s):  
Xingyi Kuang ◽  
Jie Xiong ◽  
Weili Wang ◽  
Xinyao Li ◽  
Tingting Lu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Cycle Arrest ◽  
Cell Apoptosis ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Stat3 Pathway ◽  
Cycle Arrest ◽  
Molecule Inhibitor

Abstract The serine/threonine PIM protein kinases are critical regulators of turmorigenesis in mutiple hematologic malignancies and solid cancers. We used real-time PCR to detect the expression of PIM in B-cell acute lymphocytic leukemia (B-ALL) patients, and found the expression of PIM in B-ALL patients was significantly higher than that in normal controls. SMI-4a is a pan-PIM small molecule inhibitor, and this agent exhibits demonstrable preclinical antitumour activity in a wide range of hematologic malignant cell lines. To further explore the effect of SMI-4a on B-ALL cells, B-ALL cell lines CCRF-SB and Sup-B15 were treated with this small molecule inhibitor, and the results showed that SMI-4a inhibited B-ALL cell proliferation in a dose- and time-dependent manner. Moreover, SMI-4a significantly promoted B-ALL cell apoptosis and caused cell cycle arrest in the G0/G1 phase. The results of Western blot showed that SMI-4a increased the expression of Caspase-3, Caspase-9, Bax and P21, and decreased the expression of Bcl-2 and CDK4. Furthermore, we found that SMI-4a significantly inhibits the activation of the JAK2/STAT3 pathway and HO-1 interferes with the JAK2/STAT3 pathway to inhibit SMI-4a-induced ALL cell apoptosis. Finally, xenograft experiments in NOD/SCID mice were operated to investigate the potential role of SMI-4a in B-ALL tumorigenesis in vivo. To observe the effect of SMI-4a on tumor growth in vivo, NOD/SCID mice were transplanted with B-ALL devied cells, and the tumor-bearing mice were intraperitoneally injected with saline and SMI-4a, respectively. As a result, tretment with SMI-4a resulted in a significant inhibition on tumor growth. In addition, PIM inhibtor obviously reduced the volume and weight of B-ALL cell-derived tumors. TUNEL assay revealed the proportion of apoptotic cells was higher in the SMI-4a-treated group than in the control group. Taken together, our data showed PIM inhibitor (SMI-4a) significantly inhibits the growth of B-ALL cells in vitro and in vivo and promotes apoptosis and cell cycle arrest. This suppressive effect is mediated partly through inhibiting the JAK2/STAT3 pathway activation. Disclosures No relevant conflicts of interest to declare.

scholarly journals SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0134783 ◽  
Author(s):  
Jaíra Ferreira de Vasconcellos ◽  
Angelo Brunelli Albertoni Laranjeira ◽  
Paulo C. Leal ◽  
Manoj K. Bhasin ◽  
Priscila Pini Zenatti ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Cycle Arrest

scholarly journals Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy

Leukemia ◽  
2021 ◽  
Author(s):  
Yana Pikman ◽  
Nicole Ocasio-Martinez ◽  
Gabriela Alexe ◽  
Boris Dimitrov ◽  
Samuel Kitara ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Cycle Arrest ◽  
Lymphoblastic Leukemia ◽  
Cycle Arrest ◽  
Folate Pathway ◽  
The One

AbstractDespite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers.

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