The GOD of Hematopoietic Stem Cells: A Clonal Diversity Model of the Stem Cell Compartment

Müller‐Sieburg, Christa E.; Sieburg, Hans B.

doi:10.4161/cc.5.4.2487

Cited by 26 publications

(18 citation statements)

References 60 publications

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“…In line with previous reports demonstrating considerable heterogeneity of the transplantable stem-cell compartment, 43 some heterogeneity in the activity of individual clones over time was observed irrespective of whether the mice were treated ( Figure 6). …”

Section: Stable Clonality Under Bcnu/o6-bg Selectionsupporting

confidence: 92%

Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expression

Ball

Pilz

Schmidt

et al. 2007

Blood

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Section: Stable Clonality Under Bcnu/o6-bg Selectionsupporting

confidence: 92%

Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expression

Ball

Pilz

Schmidt

et al. 2007

Blood

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“…This study shows no or very delayed lymphoid cell amplification by JAK2 V617F , which emphasizes the mild role of JAK2 in lymphocyte signaling or suggests that amplified SLAM cells are myeloid biased. 40 Intriguingly, amplification of KI SLAM cells in vehicle-treated primary recipients did not result in the same amplification of KI donor cells in secondary hosts. This result suggests that the amplification of SLAM cells by JAK2 V617F does not correlate with HSC activity.…”

Section: Discussionmentioning

confidence: 94%

JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα

Hasan

Lacout

Marty

et al. 2013

Blood

129

124

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“…This is a key question given the extreme heterogeneity of self-renewal activity displayed by individual normal HSCs in vivo [42]. By designing experiments that allowed the expansion of individual HSCs transduced with either NUP98-HOXA10 or the NUP98-HOXA10HD fusion gene to be followed, we could show that most if not all transduced HSCs could be greatly expanded within 8 to 12 days in culture, indicating that the effects seen were not due to a minor subset of HSCs.…”

Section: Discussionmentioning

confidence: 98%

Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions

Ohta

Sekulovic

Bakovic

et al. 2007

Experimental Hematology

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Objective-Strategies to expand hematopoietic stem cells (HSCs) ex vivo are of key interest. The objective of this study was to resolve if ability of HOXB4, previously documented to induce a significant expansion of HSCs in culture, may extend to other HOX genes and also to further analyze the HOX sequence requirements to achieve this effect.Methods-To investigate the ability of Nucleoporin98-Homeobox fusion genes to stimulate HSC self-renewal, we evaluated their presence in 10-to 20-day cultures of transduced mouse bone marrow cells. Stem cell recovery was measured by limiting-dilution assay for long-term competitive repopulating cells (CRU Assay).Results-These experiments revealed remarkable expansions of Nucleoporin98-Homeoboxtransduced HSCs (1000-fold to 10,000-fold over input) in contrast to the expected decline of HSCs in control cultures. Nevertheless, the Nucleoporin98-Homeobox-expanded HSCs displayed no proliferative senescence and retained normal lympho-myeloid differentiation activity and a controlled pool size in vivo. Analysis of proviral integration patterns showed the cells regenerated in vivo were highly polyclonal, indicating they had derived from a large proportion of the initially targeted HSCs. Importantly, these effects were preserved when all HOX sequences flanking the homeodomain were removed, thus defining the homeodomain as a key and independent element in the fusion.Conclusion-These findings create new possibilities for investigating HSCs biochemically and genetically and for achieving clinically significant expansion of human HSCs.The self-renewal function of hematopoietic stem cells (HSCs) is essential to their ability to sustain lifelong hematopoiesis and to regenerate the hematopoietic system after myeloablative treatments. This property is the basis of an increasing range of applications of HSC transplants to treat various malignant and genetic disorders [1,2]. Further improvements in the safety and therapeutic utility of HSC transplants can be readily envisaged if robust methods for largescale ex vivo expansion of HSCs were available. For example, the low absolute numbers of HSCs in most cord blood samples [3] [4] restrict the clinical utility of these products. A method for significantly expanding HSCs could not only address these insufficiencies but also broaden the exploitation of reduced conditioning regimens and associated therapeutic benefits.One approach that has allowed some HSC expansion in vitro to be achieved has focused on the identification of optimized combinations and concentrations of externally acting growth factors and related molecules [5][6][7][8][9][10][11][12]. A complementary approach has been to identify intrinsic regulators such as transcription factors [13] and key mediators of signaling pathways [14,15] that can be manipulated to activate or promote HSC self-renewal divisions. A striking example of the latter strategy is the use of retrovirally engineered overexpression of the homeobox transcription factor HOXB4 to stimulate expansions of HSC numb...

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The GOD of Hematopoietic Stem Cells: A Clonal Diversity Model of the Stem Cell Compartment

Cited by 26 publications

References 60 publications

Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expression

Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expression

JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα

Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions

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