scholarly journals Raf-Induced Cell Cycle Progression in Human TF-1 Hematopoietic Cells

Cell Cycle ◽  
2002 ◽  
Vol 1 (3) ◽  
pp. 218-224 ◽  
Author(s):  
Fumin Chang ◽  
Linda S. Steelman ◽  
James A McCubrey
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Cycle Progression

Homing efficiency, cell cycle kinetics, and survival of quiescent and cycling human CD34+ cells transplanted into conditioned NOD/SCID recipients

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1585-1593 ◽  
Author(s):  
Anna Jetmore ◽  
P. Artur Plett ◽  
Xia Tong ◽  
Frances M. Wolber ◽  
Robert Breese ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Nonobese Diabetic ◽  
Cd34 Cells ◽  
G1 Cells ◽  
Active Proliferation

Differences in engraftment potential of hematopoietic stem cells (HSCs) in distinct phases of cell cycle may result from the inability of cycling cells to home to the bone marrow (BM) and may be influenced by the rate of entry of BM-homed HSCs into cell cycle. Alternatively, preferential apoptosis of cycling cells may contribute to their low engraftment potential. This study examined homing, cell cycle progression, and survival of human hematopoietic cells transplanted into nonobese diabetic severe combined immunodeficient (NOD/SCID) recipients. At 40 hours after transplantation (AT), only 1% of CD34+ cells, or their G0(G0CD34+) or G1(G1CD34+) subfractions, was detected in the BM of recipient mice, suggesting that homing of engrafting cells to the BM was not specific. BM of NOD/SCID mice receiving grafts containing approximately 50% CD34+ cells harbored similar numbers of CD34+ and CD34− cells, indicating that CD34+ cells did not preferentially traffic to the BM. Although more than 64% of human hematopoietic cells cycled in culture at 40 hours, more than 92% of cells recovered from NOD/SCID marrow were quiescent. Interestingly, more apoptotic human cells were detected at 40 hours AT in the BM of mice that received xenografts of expanded cells in S/G2+M than in recipients of G0/G1 cells (34.6% ± 5.9% and 17.1% ± 6.3%, respectively; P < .01). These results suggest that active proliferation inhibition in the BM of irradiated recipients maintains mitotic quiescence of transplanted HSCs early AT and may trigger apoptosis of cycling cells. These data also illustrate that trafficking of transplanted cells to the BM is not selective, but lodgment of BM-homed cells may be specific.

scholarly journals Ability of the Activated PI3K/Akt Oncoproteins to Synergize with MEK1 and Induce Cell Cycle Progression and Abrogate the Cytokine-Dependence of Hematopoietic Cells

Cell Cycle ◽  
2004 ◽  
Vol 3 (4) ◽  
pp. 501-510 ◽  
Author(s):  
John G. Shelton ◽  
William L. Blalock ◽  
Edmond R. White ◽  
Linda S. Steelman ◽  
James A McCubrey
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Cycle Progression ◽  
Induce Cell Cycle Progression

scholarly journals Synergy between PI3K/Akt and Raf/MEK/ERK Pathways in IGF-1R Mediated Cell Cycle Progression and Prevention of Apoptosis in Hematopoietic Cells

Cell Cycle ◽  
2004 ◽  
Vol 3 (3) ◽  
pp. 370-377 ◽  
Author(s):  
John G. Shelton ◽  
Linda S. Steelman ◽  
Edmond R. White ◽  
James A McCubrey
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Cycle Progression

Phosphorylation of Runx1 by Cyclin-Dependent Kinases Regulates Its Interaction with HDAC1 and HDAC3.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1381-1381 ◽  
Author(s):  
Hong Guo ◽  
Alan D. Friedman
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Cyclin D3 ◽  
Mrna Levels ◽  
Cycle Progression ◽  
Hematopoietic Stem ◽  
Protein Levels ◽  
Cdk Phosphorylation ◽  
Regulation Of Cell Cycle

Abstract Runx1/AML1 is a key regulator of hematopoiesis and leukemic transformation, as RUNX1(−/−) mice do not develop definitive hematopoietic stem cells, and sever alleukemic oncogenes, e.g. AML1-ETO, CBFβ-SMMHC, or TEL-AML1, inhibit Runx1activities. We have investigated regulation of cell cycle progression by Runx1. Runx1stimulates G1 to S cell cycle progression in hematopoietic cell lines and in transduced myeloid progenitors, and inhibition of Runx1 by CBFβ-SMMHC or AML1-ETO slows G1 progression. Runx1 induces cdk4 and cyclin D3 transcription, and exogenous cdk4, cyclin D2, or c-Myc overcomes inhibition of G1 progression by CBF oncoproteins. In addition to regulating cell cycle progression, Runx1 protein levels are themselves increased as hematopoietic cells progress from G1 to S to G2/M, though mRNA levels remain constant. Runx1 contains three consensus cdk sites, (S/T)PX(R/K), S48, S303, and S424, and using phospho-specific antisera we find that each of these is modified in hematopoietic cells. Mutation of these serines to aspartic acid, mimicking phosphorylation, increases trans-activation of a reporter containing four CBF sites or the TCRβ promoter, whereas mutation to alanine reduces trans-activation. p300 interacts similarly with Runx1(tripleA) and Runx1(tripleD). We have now evaluated interaction of HDACs1–8 with these variants and Runx1 and find that both HDAC1 and HDAC3 have reduced affinity for RUNX1(tripleD), as assessed by co-immunoprecipitation from transiently transfected 293T cells. Evaluation of single serine residue mutants (S48D, S303D, and S424D) demonstrates reduced affinity of HDAC1 or HDAC3 specifically for the Runx1(S424D) mutant, consistent with previous mapping of the Runx1:HDAC1 and Runx1:HDAC3 interactions to this region of Runx1. Thus, cdk phosphorylation of Runx1 S424 reduces affinity for HDAC1 and HDAC3, increasing Runx1 trans-activation potency. Regulation of Runx1 activity by cdks may control key developmental processes, including expansion of definitive HSC during development and regulation of the balance between adult HSC quiescence and proliferation.

AML1-ETO9a, an Alternatively Spliced Form of AML1-ETO, Collaborates with AML1-ETO To Promote Leukemogenesis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 661-661
Author(s):  
Ming Yan ◽  
Yang Wang ◽  
Luke F. Peterson ◽  
Eiki Kanbe ◽  
Anita Boyapati ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Chromosome Translocation ◽  
Full Length ◽  
Hematopoietic Progenitor Cell ◽  
Cycle Progression ◽  
Negative Effect ◽  
Alternatively Spliced ◽  
Progenitor Cell Line

Abstract t(8;21) is a common chromosome translocation in acute myeloid leukemia (AML). AML1-ETO is the fusion protein produced by t(8;21). Results from our work and others indicate that full length AML1-ETO is not leukemogenic and needs additional mutations to promote leukemia. Most recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, that lacks the C-terminal NHR3 and NHR4 domains of AML1-ETO. Here, we report that unlike the negative effect of full length AML1-ETO in cell cycle progression, AML1-ETO9a enhances cell proliferation by shortening G1 phase of cell cycle in the IL-3 dependent multipotent hematopoietic progenitor cell line FDCPmix. Using retroviral mediated gene expression in murine hematopoietic cells and bone marrow transplantation in mice, we have demonstrated that AML1-ETO9a is highly leukemogenic. Most importantly, we show that AML1-ETO9a expression in transgenic MRP-8 AML1-ETO hematopoietic cells results in earlier onset of AML than AML1-ETO9a expression alone controls. Furthermore, the presence of full length AML1-ETO also alters the phenotype of leukemia progenitor cells from CD34- to CD34+. These results suggest that the alternatively spliced form AML1-ETO9a cooperates with full length AML1-ETO in leukemogenesis when coexpressed in t(8;21) patients.

Internal Tandem Duplication of Flt3 (ITD-Flt3) Bypasses Growth Factor Mediated Survivin Expression, while Disruption of Survivin Accelerates Cell Death in Hematopoietic Cells Expressing ITD-Flt3.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1256-1256
Author(s):  
Seiji Fukuda ◽  
Louis M. Pelus
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Survival ◽  
Cell Cycle Progression ◽  
Hematopoietic Cells ◽  
Survivin Expression ◽  
Hematopoietic Growth Factors ◽  
Cycle Progression ◽  
Cd34 Cells

Abstract The inhibitor of apoptosis protein Survivin is barely detectable in normal adult tissues but is over-expressed in almost all cancers and hematopoietic malignancies and confers resistance to apoptosis and aberrant cell proliferation. We have shown that hematopoietic growth factors induce Survivin expression in normal CD34+ cells in both cell cycle dependent and independent fashion and that oncogenic Ras can enhance Survivin expression independent of growth factor stimulation. In addition, over-expression of Survivin blocks apoptosis of hematopoietic progenitor cells through a p21WAF1/Cip1 (p21) dependent mechanism. However the mechanisms responsible for Survivin overexpression in malignant hematopoietic cells is poorly understood. Flt3 is a type III tyrosine kinase receptor expressed mainly in the primitive hematopoietic compartment. Internal tandem duplication (ITD) mutations of the Flt3 gene that activate the Flt3 tyrosine kinase are frequently found in patients with AML and associated with poor prognosis. Furthermore, their ectopic expression in IL-3 dependent Ba/F3 cells results in IL-3-independent proliferation and a myeloproliferative disease in mice. In order to understand the mechanism by which ITD-Flt3 enhances cell survival, we examined whether ITD-Flt3 can bypass Survivin up-regulation independent of hematopoietic growth factors and if Survivin lies down stream of ITD-Flt3 in prolonging cell survival. Incubation of primary umbilical cord blood CD34+ cells with Flt3 ligand induced Survivin expression, indicating that Survivin lies down stream of Flt3 signaling pathways in CD34+ cells. While Survivin expression was comparable in Ba/F3 cells expressing ITD-Flt3 (W51, W73 and W78 mutants, kindly provided by Dr. DG Gilliland) and wild-type Flt3 when maintained in the presence of IL-3, ITD-Flt3 prevented down-modulation of Survivin expression induced by IL-3 withdrawal even during G0/G1 phase of cell cycle, suggesting that up-regulation of Survivin is not a consequence of cell cycle progression associated with ITD-Flt3 expression. The increase in Survivin by ITD-Flt3 was associated with reduced active caspase-3 and prolonged cell survival coincident with induction of p21 expression and Tyrosine 15 phosphorylation of CDK1 (Cdc2), which have been implicated in anti-apoptosis. These results are consistent with a p21 dependent anti-apoptosis effect of Survivin in primary hematopoietic progenitor cells and suggest the involvement of Survivin-p21 and CDK1 in ITD-Flt3 mediated cell survival. Overexpression of dominant negative T34A Survivin inhibits the enhanced survival induced by ITD-Flt3 in Ba/F3 cells following IL-3 withdrawal, suggesting that the survival effect of ITD-Flt3 is mediated by Survivin. Similar to ITD-Flt3, overexpression of ectopic wild-type Survivin results in enhanced cell survival in Ba/F3 cells but failed to induce cell cycle progression and IL-3-independent proliferation, indicating that Survivin alone is not sufficient for induction of growth factor independent proliferation and the cell cycle enhancing effect of ITD-Flt3. In summary, our findings indicate that ITD-Flt3 up-regulates Survivin expression independent of hematopoietic growth factors and that the ITD-Flt3/Survivin axis provides a survival advantage in transformed hematopoietic cells. Disruption of these pathways may increase apoptosis of malignant hematopoietic cells and provide therapeutic benefit.

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