Interleukin 3 or interleukin 1 abrogates the reconstituting ability of hematopoietic stem cells.

Yonemura, Yuji; Ku, Hsun Teresa; Hirayama, Fumiya; Souza, Lawrence M.; Ogawa, Makio

doi:10.1073/pnas.93.9.4040

Cited by 181 publications

(102 citation statements)

References 27 publications

(5 reference statements)

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“…Protein-protein interactions involving the rhd and ETS proteins, C/EBP, or CBFb are not shown ALL with a t(5;14) abnormality remains the only ALL identi®ed thus far that expresses IL-3 (Grimaldi and Meeker, 1989;Meeker et al, 1990). Although IL-3 has been shown to have an inhibitory role on the growth of B cells under certain in vitro conditions (Yonemura et al, 1996), we have no evidence that repression of IL-3 expression by TEL-AML1 in B cells could have functional consequences.…”

Section: Discussioncontrasting

confidence: 59%

Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter

et al. 1999

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A cytogenetically cryptic (12;21) translocation is the most common molecular abnormality identi®ed in childhood acute lymphoblastic leukemia (ALL), and it generates a chimeric TEL-AML1 protein. Fusion of the Helix-Loop-Helix (HLH) (also called the pointed) domain of TEL to AML1 has been suggested to convert AML1 from a transcriptional activator to a repressor. To de®ne the structural features of this chimeric protein required for repression, we analysed the transcriptional activity of a series of TEL-AML1 mutants on the AML1-responsive interleukin-3 (IL-3) promoter, a potentially relevant gene target. Our results demonstrate that TEL-AML1 represses basal IL-3 promoter activity in lymphoid cells, and deletion mutant analysis identi®ed three distinct domains of TEL-AML1 that are required for repression; the HLH (pointed) motif contained in the TEL portion of TEL-AML1, and both the runt homology domain (Rhd) and the 74 amino acids downstream of the Rhd that are present in the AML1 portion of the fusion protein. Although AML1B (and a shorter AML1 isoform, AML1A) have transcriptional activating activity on the IL-3 promoter, fusion of the AML1 gene to the TEL gene generates a repressor of IL-3 expression. Consistent with this activity, freshly isolated human ALL cells that contain TEL-AML1 do not express IL-3.

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Section: Discussioncontrasting

confidence: 59%

Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter

et al. 1999

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“…These cells tend to differentiate in tissue cultures supplemented with growth factors, thereby reducing their capacity to repopulate bone marrow and radioprotect recipient mice. 39,40 Growth factors are required to stimulate cell division in culture, which is a prerequisite for integration of retroviral sequences into the genome. In the present study, we found a total culture period of 6 days suitable while prolongation to 8 days resulted in engraftment failure.…”

Section: Then Spun Down and Resuspended In Medium With Or Without Vermentioning

confidence: 99%

Drug selection of MDR1-transduced hematopoietic cells ex vivo increases transgene expression and chemoresistance in reconstituted bone marrow in mice

et al. 2000

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“…The negative effect of IL3 for LTC-IC amplification could be attributed to an increased induction of proliferation and maturation of primitive stem cells at the expense of the self-renewal capacity, as recently demonstrated. [19][20][21] The experiments described here throw new light on the kinetics of expansion of primitive stem cells. Indeed, data reported so far on LTC-IC amplification are limited to incubation periods of a few weeks.…”

Section: Figurementioning

confidence: 99%

Differential growth factor requirement of primitive cord blood hematopoietic stem cell for self-renewal and amplification vs proliferation and differentiation

et al. 1998

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Cord blood (CB) is an attractive alternative to bone marrow or peripheral blood as a source of transplantable hematopoietic tissue. However, because of the reduced volume, the stem cell content is limited; therefore its use as a graft for adult patients might require ex vivo manipulations. Two systems have been described that identify these stem cell populations in vitro in both mice and humans: (1) the long-term culture-initiating cells (LTC-IC), thus named because of their ability to support the growth of hematopoietic colonies (colony-forming cell (CFC)) for 5-6 weeks when co-cultured on stromal layers; (2) the generation of hematopoietic progenitors (CFC) from stroma-free liquid cultures for extended periods of time, which provides further indirect evidence of the presence of primitive stem cells. Both systems detect largely overlapping but not identical populations of stem cells. Thus the identification of the growth factor requirements for the maintenance and amplification of both systems is relevant. On this basis, analysis of the effects of 18 cytokine combinations on stroma-free liquid cultures of CB CD34 + cells, showed that: (1) after 7-and 14 day-incubation periods, several growth factor combinations expanded the LTC-IC pool to a similar extent; as compared to the LTC-IC, the generation of CFC was not impressive; (2) time-course analysis of the LTC-IC expansion demonstrated that, by extending the incubation period, only a few growth factor combinations, containing FL, TPO, KL and IL6, could support a further, increasingly greater LTC-IC expansion (up to 270 000-fold of the initial value). In similar culture conditions, CFC production underwent continuous expansion, which persisted for over 7 months and reached values of one million-fold of the initial value. The simultaneous presence of FL and TPO was both necessary and sufficient to support this phenomenon. The addition of KL ± IL6 did not appear to substantially modify the extent of LTC-IC expansion; nevertheless, it played an important role in sustaining an even more massive and prolonged output of CFU-GM, CFU-Mk and BFU/CFU-GEMM (up to 100 million-fold); (3) the presence of IL3 was found to be negative, in that it inhibited both the extent of LTC-IC expansion and the long-term generation of CFC. Thus, FL and TPO appear as two unique growth factors that preferentially support the self-renewal of primitive stem cells; the additional presence of KL and IL6 seems to enhance the proliferative potential of at least one subpopulation of daughter stem cells, which may follow three differentiation pathways. Far from being definitive, our data demonstrated that massive stem cell expansion, in cord blood, can be obtained in reasonably well-defined culture conditions. This could represent an initial step towards larger scale cultures for transplantation and gene therapy protocols.

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Interleukin 3 or interleukin 1 abrogates the reconstituting ability of hematopoietic stem cells.

Cited by 181 publications

References 27 publications

Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter

Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter

Drug selection of MDR1-transduced hematopoietic cells ex vivo increases transgene expression and chemoresistance in reconstituted bone marrow in mice

Differential growth factor requirement of primitive cord blood hematopoietic stem cell for self-renewal and amplification vs proliferation and differentiation

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