FLT3/ITD Expression Increases Expansion, Survival and Entry into Cell Cycle of Human Hematopoietic Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 484-484
Author(s):  
Li Li ◽  
Obdulio Piloto ◽  
Kyu-Tae Kim ◽  
Zhaohui Ye ◽  
Bao Nguyen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Tyrosine Kinase ◽  
Cell Cycle Regulation ◽  
Cyclin D3 ◽  
Leukemic Transformation ◽  
Hematopoietic Stem ◽  
Activating Mutations ◽  
Juxtamembrane Region ◽  
Cycle Regulation

Abstract FMS-like tyrosine kinase-3 (FLT3) is a Class III receptor tyrosine kinase that is important for normal hematopoiesis. Activating mutations of FLT3 by internal tandem duplications (ITDs) in the juxtamembrane region are the most common molecular aberrations found in acute myeloid leukemia (AML). The contributions of FLT3 activating mutations in the leukemic transformation of normal human hematopoietic stem/progenitor cells (HSCs) have not yet been fully elucidated. In this study, using a single lentiviral vector containing two promoters, we achieved consistent and efficient coexpression of FLT3/ITD and green fluorescent protein (GFP) in transduced human CD34+ HSCs. When cultured in medium containing SCF, TPO and FLT3 ligand (FL), FLT3/ITD-transduced cells survived with enhanced self-renewal and survival potential, which was not affected by the withdrawal of FL. These cells retained a surface immunophenotype typical of HSCs (CD34+CD38−). Compared to cells transduced with a vector expressing GFP alone, FLT3/ITD-transduced HSCs had a higher fraction of cells in cell cycle. Clonogenic assays showed that FLT3/ITD-transduced HSCs produced fewer CFU-GM, implying that they were at least partially blocked in their ability to differentiate along the myeloid lineage. FLT3/ITD-transduced HSCs were more sensitive to the induction of cytotoxicity by CEP-701, a selective FLT3 inhibitor. In the FLT3/ITD-transduced HSCs, we detected increased expression of Pim-1, a serine/threonine kinase with an important role in cell survival, proliferation and differentiation, c-myc, a transcription factor involved in cell proliferation and cell cycle regulation, and Cyclin D3, a key factor in cell cycle regulation, each of which may contribute to the altered genetic program instituted by FLT3/ITD signaling. These results together indicate that FLT3/ITD mutations may contribute to leukemic transformation of normal HSCs by prolonging survival, promoting proliferation, and blocking differentiation. CEP-701 may act as a potent agent for AML stem cells harboring FLT3/ITD mutations.

scholarly journals Cell cycle regulation in hematopoietic stem cells

2011 ◽  
Vol 195 (5) ◽  
pp. 709-720 ◽  
Author(s):  
Eric M. Pietras ◽  
Matthew R. Warr ◽  
Emmanuelle Passegué
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Regulation ◽  
Critical Role ◽  
Cellular Damage ◽  
Fetal Life ◽  
Extrinsic Factors ◽  
Hematopoietic Stem ◽  
Cycle Regulation

Hematopoietic stem cells (HSCs) give rise to all lineages of blood cells. Because HSCs must persist for a lifetime, the balance between their proliferation and quiescence is carefully regulated to ensure blood homeostasis while limiting cellular damage. Cell cycle regulation therefore plays a critical role in controlling HSC function during both fetal life and in the adult. The cell cycle activity of HSCs is carefully modulated by a complex interplay between cell-intrinsic mechanisms and cell-extrinsic factors produced by the microenvironment. This fine-tuned regulatory network may become altered with age, leading to aberrant HSC cell cycle regulation, degraded HSC function, and hematological malignancy.

Cell Cycle Regulation and Cell Fate Decisions in Hematopoietic Stem Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1349-1349
Author(s):  
Emmanuelle Passegue ◽  
Amy J. Wagers ◽  
Sylvie Giuriato ◽  
Wade C. Anderson ◽  
Irving L. Weissman
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Fate ◽  
Cell Cycle Regulation ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Cycle Regulation

Abstract The blood is a perpetually renewing tissue seeded by a rare population of adult bone marrow hematopoietic stem cells (HSC). During steady-state hematopoiesis, the HSC population is relatively quiescent but constantly maintains a low numbers of cycling cells that differentiate to produce the various lineage of mature blood cells. However, in response to hematological stress, the entire HSC population can be recruited into cycle to self-renew and regenerate the blood-forming system. HSC proliferation is therefore highly adaptative and requires appropriate regulation of cell cycle progression to drive both differentiation-associated and self-renewal-associated proliferation, without depletion of the stem cell pool. Although the molecular events controlling HSC proliferation are still poorly understood, they are likely determined, at least in part, by regulated expression and/or function of components and regulators of the cell cycle machinery. Here, we demonstrate that the long-term self-renewing HSC (defined as Lin−/c-Kit+/Sca-1+/Thy1.1int/Flk2−) exists in two distinct states that are both equally important for their in vivo functions as stem cells: a numerically dominant quiescent state, which is critical for HSC function in hematopoietic reconstitution; and a proliferative state, which represents almost a fourth of this population and is essential for HSC functions in differentiation and self-renewal. We show that when HSC exit quiescence and enter G1 as a prelude to cell division, at least two critical events occur: first, during the G1 and subsequent S-G2/M phases, they temporarily lose efficient in vivo engraftment activity, while retaining in vitro differentiation potential; and second, they select the particular cell cycle proteins that are associated with specific developmental outcomes (self-renewal vs. differentiation) and developmental fates (myeloid vs. lymphoid). Together, these findings provide a direct link between HSC proliferation, cell cycle regulation and cell fate decisions that have critical implications for both the therapeutic use of HSC and the understanding of leukemic transformation.

Cell Cycle Regulation in Human Hematopoietic Stem Cells: From Isolation to Activation

2002 ◽  
Vol 43 (3) ◽  
pp. 493-501 ◽  
Author(s):  
Maria Marone ◽  
Daniela de Ritis ◽  
Giuseppina Bonanno ◽  
Simona Mozzetti ◽  
Sergio Rutella ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Regulation ◽  
Hematopoietic Stem ◽  
Cycle Regulation

scholarly journals Cell cycle regulation in hematopoietic stem cells

2011 ◽  
Vol 208 (13) ◽  
pp. i34-i34 ◽  
Author(s):  
Eric M. Pietras ◽  
Matthew R. Warr ◽  
Emmanuelle Passegué
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Cycle Regulation ◽  
Hematopoietic Stem ◽  
Cycle Regulation

Cell Cycle Regulation in Hematopoietic Stem/progenitor Cells

2004 ◽  
Vol 5 (1) ◽  
pp. 50-60
Author(s):  
Hirokazu Tanaka . ◽  
Itaru Matsumura . ◽  
Yuzuru Kanakura .
Keyword(s):  
Cell Cycle ◽  
Progenitor Cells ◽  
Cell Cycle Regulation ◽  
Hematopoietic Stem ◽  
Cycle Regulation

scholarly journals Increased proliferation and altered cell cycle regulation in pancreatic stem cells derived from patients with congenital hyperinsulinism

PLoS ONE ◽  
2019 ◽  
Vol 14 (9) ◽  
pp. e0222350 ◽  
Author(s):  
Sophie G. Kellaway ◽  
Karolina Mosinska ◽  
Zainaba Mohamed ◽  
Alexander Ryan ◽  
Stephen Richardson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Regulation ◽  
Congenital Hyperinsulinism ◽  
Pancreatic Stem Cells ◽  
Altered Cell ◽  
Cycle Regulation

scholarly journals Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 397
Author(s):  
Cheuk Yiu Tenny Chung ◽  
Paulisally Hau Yi Lo ◽  
Kenneth Ka Ho Lee
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Gamma Irradiation ◽  
Cellular Senescence ◽  
Cell Cycle Regulation ◽  
Cell Cycle Progression ◽  
Embryonic Stem ◽  
Cycle Progression ◽  
Cycle Regulation

BRISC and BRCA1-A complex member 2 (Babam2) plays an essential role in promoting cell cycle progression and preventing cellular senescence. Babam2-deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of Babam2 in ESCs would enable us to understand the mechanism of Babam2 in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated Babam2 knockout (Babam2−/−) mESCs to investigate the function of Babam2 in mESCs. We demonstrated that the loss of Babam2 in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, CDC25A and CDK2, were found to be degraded in Babam2−/− mESCs following gamma irradiation. In addition, Babam2−/− mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in Babam2−/− mESCs. In summary, Babam2 maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.

scholarly journals The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation

Cancer Cell ◽  
2018 ◽  
Vol 34 (4) ◽  
pp. 626-642.e8 ◽  
Author(s):  
Natalia Martinez-Soria ◽  
Lynsey McKenzie ◽  
Julia Draper ◽  
Anetta Ptasinska ◽  
Hasan Issa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Regulation ◽  
Leukemic Transformation ◽  
Cycle Regulation ◽  
Oncogenic Transcription Factor

Oncogenic Nras Increases Hematopoietic Stem Cell Proliferation and Self-Renewal Through a Bimodal Effect

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 119-119
Author(s):  
Qing Li ◽  
Natacha Bohin ◽  
Tiffany Wen ◽  
Kevin M. Shannon ◽  
Sean J. Morrison
Keyword(s):  
Stem Cells ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasm ◽  
Mek Inhibitor ◽  
Ras Signaling ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Activating Mutations ◽  
Cycle Regulation

Abstract Abstract 119 Accumulating evidence suggests that most leukemias are initiated by rare leukemic stem cells (LSC) that are transformed from the normal hematopoietic stem cells and progenitors (HSC/P) by genetic lesions that lead to activation of oncogenes and inactivation of tumor suppressor genes. However, the signaling mechanisms by which these genes transform HSC/P into LSC are poorly understood. Activating mutations of NRAS and KRAS are highly prevalent in acute myeloid leukemia (AML), some myeloproliferative neoplasm (MPN) and myelodysplastic syndromes (MDS). In addition other leukemia associated genetic lesions, such as the BCR-ABL fusion, PTPN11 mutations, FLT3 internal tandem duplications, and NF1 inactivation all deregulate Ras signaling. We previously developed a mouse strain that conditionally expresses an oncogenic NrasG12D allele from the endogenous locus. This consistently resulted in an indolent MPD with delayed onset and prolonged survival in Mx1-cre, NrasG12D/+ mice (referred to as NrasG12D). Oncogenic NrasG12D, however, cooperated with the MOL4070LTR retrovirus to induce AMLs that share molecular and morphologic features with human M4/M5 AML. Here we report that NrasG12D directly affects HSC/P functions. While normal HSCs must remain quiescent to maintain the long term self-renewal capacity and mutations that drive HSC into cycle often lead to HSC depletion, NrasG12D increased HSC proliferation but at the same time increased the self-renewal and competitiveness of HSCs. Serial transplantations revealed that NrasG12D HSCs were able to give higher level of reconstitution than wild-type (WT) HSCs and gave rise to long term multi-lineage reconstitution in lethally irradiated mice after up to four rounds of transplantation while WT HSCs failed to reconstitute beyond two rounds. These effects were not associated with the development of leukemia suggesting oncogenic Nras dys-regulates HSC at a pre-leukemic stage and therefore plays an important role in leukemia initiation. Using histone-2B-GFP (H2B-GFP) label-retaining assays, we further detected a “bimodal” effect of NrasG12D on HSCs: NrasG12D induced a subpopulation of rapid “cycling” HSCs that lost GFP labeling and reconstitution activity faster than WT HSC but another HSC subpopulation that remained more “quiescent” than WT HSCs and retained higher reconstitution when transplanted to irradiated mice. The canonical Ras effector, ERK, was not activated in NrasG12D HSC/Ps and inhibition of ERK with a MEK inhibitor, PD325901, did not have any effect on the Nras induced increase of HSC proliferation. Stat5, on the other hand, was significantly activated in NrasG12D HSC/Ps and heterozygous knockout of Stat5ab abolished the increased proliferation in NrasG12D HSCs, suggesting that Stat5 signaling mediates at least part of the Nras induced increase in HSC proliferation. Nras is thus the first signaling pathway that simultaneously increases HSC proliferation, self-renewal and competitiveness without inducing frank leukemogenesis. This is likely through a “bimodal” effect of Nras signaling on HSC cell cycle regulation. Our studies also identified Stat5 as a novel therapeutic target to inhibit early events in Ras mediated leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

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