Rb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment

Walkley, Carl R.; Shea, Jeremy; Sims, Natalie A.; Purton, Louise E.; Orkin, Stuart H.

doi:10.1016/j.cell.2007.03.055

Cited by 376 publications

(327 citation statements)

References 79 publications

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“…Our data demonstrating differences in the expression of various critical adhesion molecules known to be associated with the engraftment and homing potential of WT stem/progenitor cells clearly illustrates this point. Others have also reported a lack of correlation between phenotypic markers and function of stem cells in both mutant mice as well as upon perturbing normal steady-state hematopoiesis [39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

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Objective-Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells.Results-Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1 + Lin − cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo. Interestingly, a significant increase in expression of adhesion molecules, known to coincide with the homing potential of wild-type bone marrow cells is also observed on the surface of SFK −/− cells, although, this increase did not affect the homing potential of more primitive Lin − Sca-1 + SFK −/− cells. The stem cell-repopulating defect observed in mice transplanted with SFK −/− bone marrow cells is due to the loss of Lyn Src kinase, because deficiency of Lyn, but not Hck or Fgr, recapitulated the long-term stem cell defect observed in mice transplanted with SFK −/− bone marrow cells.Conclusions-Taken together, our results demonstrate an essential role for Lyn kinase in positively regulating the long-term and multilineage engraftment of stem cells, which is distinct from its role in mature B cells and myeloid cells. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptEngraftment and reconstitution of normal hematopoiesis following transplantation of hematopoietic stem/progenitor (HSC/P) cells is the product of several important parameters, including the ability of hematopoietic stem cells (HSC) to home to, anchor within, and survive in specialized bone marrow (BM) niches, followed by timely proliferation and selfrenewal of stem cells for life-long hematopoiesis. While investigators have sought to understand the mechanisms behind each individual step, engraftment remains largely undefined.Besides homing and anchoring of HSC/P cells following transplantation, signals emanating from cytokine receptors also play a prominent role in regulating HSC/P cell growth and survival. In general, both positive and negative signals induced in response to cytokine stimulation contribute to this process. Deregulated signaling downstream from cytokine receptors can alter the growth and differentiation of these cells and, in some cases, contribute to leukemogenesis. Examples of molecules that are activated in response to hematopoietic growth factors include, but are not limited to, nonreceptor tyrosine kinases, such as Src family kinases (SFKs). SFKs function in signal transduction from growth factor receptors for granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, IL-5, stem cell factor (SCF), erythropoietin, M-CSF, G-CSF, thrombopoietin, and Flt3 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Although diverse cytokine receptors activat...

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Section: Discussionmentioning

confidence: 99%

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Orschell

Borneo

Munugalavadla

et al. 2008

Experimental Hematology

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“…For instance, no hematopoietic phenotype was observed in p130-deficient mice (Cobrinik et al, 1996), and p107 deletion resulted in only a mild myeloid hyperplasia (LeCouter et al, 1998). Removal of pRb had also no effect on HSC self-renewal as assessed by serial transplantation (Walkley and Orkin 2006), and although pRb-deficient mice exhibited myeloid expansion, this was shown to be a non-cell autonomous effect (Walkley and Orkin 2006;Walkley et al, 2007). Strikingly, however, conditional deletion of all three Rb family members in of a constitutively low level of cell cycle activity for proper function of the blood system during adult life.…”

Section: Distinct Cell Cycle Activities In Fetal and Adult Hscsmentioning

confidence: 99%

Cell cycle regulation in hematopoietic stem cells

Pietras¹,

Warr²,

Passegué³

2011

J Exp Med

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“…These results confirm the lack of leukemogenic potential of Pten;Rag1 null hematopoietic cells. The absence of myeloid leukemia in both Pten null and Pten;Rag1 null mice suggests that the AML phenotype observed in Pten loxP/loxP ;Mx-1-Cre + mice may result from a higher proportion of hematopoietic stem cells (HSCs) carrying Pten deletion (14, 16), a nichedependent effect (15,17), and/or effects of pIpC and pIpCinduced IFN activation on HSCs (18,19).…”

Section: Recombination-activating Gene 1 Deletion Abolishes Leukemiamentioning

confidence: 99%

Suppression of leukemia development caused by PTEN loss

Guo

Schubbert

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Multiple genetic or molecular alterations are known to be associated with cancer stem cell formation and cancer development. Targeting such alterations, therefore, may lead to cancer prevention. By crossing our previously established phosphatase and tensin homolog (Pten)-null acute T-lymphoblastic leukemia (T-ALL) model onto the recombination-activating gene 1 −/− background, we show that the lack of variable, diversity and joining [V(D)J] recombination completely abolishes the Tcrα/δ-c-myc translocation and T-ALL development, regardless of β-catenin activation. We identify mammalian target of rapamycin (mTOR) as a regulator of β-selection. Rapamycin, an mTOR-specific inhibitor, alters nutrient sensing and blocks T-cell differentiation from CD4 − CD8 − to CD4 + CD8 + , the stage where the Tcrα/δ-c-myc translocation occurs. Long-term rapamycin treatment of preleukemic Pten-null mice prevents Tcrα/δ-c-myc translocation and leukemia stem cell (LSC) formation, and it halts T-ALL development. However, rapamycin alone fails to inhibit mTOR signaling in the c-Kit mid CD3 + Lin − population enriched for LSCs and eliminate these cells. Our results support the idea that preventing LSC formation and selectively targeting LSCs are promising approaches for antileukemia therapies. T -lymphoblastic leukemia (T-ALL) is a common hematological malignancy that is associated with poor prognosis compared with other ALLs and is often fatal without effective treatment (1). Activating mutations in Notch gene homolog 1 (NOTCH1) are reported in 34-71% of human T-ALL patients (2, 3), whereas deletion or mutations of the phosphatase and tensin homolog (PTEN). tumor suppressor gene have recently been detected in 8-63% of pediatric T-ALL patients (3-6). The mutation status of NOTCH1 and PTEN can divide pediatric T-ALL patients into three groups: (i) those with both NOTCH1 and PTEN mutations, (ii) those with NOTCH1/F-box and WD repeat domain containing 7 (FBXW7) mutations, and (iii) those with only PTEN mutations (3). Interestingly, constitutive activation of the NOTCH signaling pathway is known to down-regulate PTEN expression (5, 7), suggesting that PTEN and its controlled PI3K/v-akt murine thymoma viral oncogene homolog (AKT)/mTOR pathway are critical for the etiology of human T-ALL. Furthermore, PTEN deletion seems to be correlated with poor response to chemotherapy (6) and resistance to pharmacological inhibition of NOTCH1 (5). Therefore, understanding the molecular mechanisms of PTEN-mediated T-ALL pathogenesis and drug resistance is a critical step to improving T-ALL therapeutics.To investigate the molecular and cellular mechanisms associated with PTEN-controlled T-ALL pathogenesis and therapeutic resistance, we have recently developed a Pten loxP/loxP ;VE-CadherinCre + ;Rosa26 loxP-stop-loxP -LacZ + (Pten null) T-ALL mouse model by conditional deletion of Pten in a subset of fetal liver hematopoietic stem cells (8). The resulting animals develop a transient myeloproliferative disorder followed by T-ALL with 100% penetrance. Besides Pt...

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Rb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment

Cited by 376 publications

References 79 publications

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Cell cycle regulation in hematopoietic stem cells

Suppression of leukemia development caused by PTEN loss

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