Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

Xiao, Pengnan; Dolinska, Monika B.; Sandhow, Lakshmi; Kondō, Makoto; Johansson, Anne; Bouderlique, Thibault; Ying, Zhao; Li, Xidan; Dimitriou, Marios; Rassidakis, George Z.; Hellström‐Lindberg, Eva; Minato, Nagahiro; Walfridsson, Julian; Scadden, David T.; Sigvardsson, Mikael; Qian, Hong

doi:10.1182/bloodadvances.2017013599

Cited by 32 publications

(41 citation statements)

References 61 publications

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“…Furthermore, Sipa1 reduction in AML MSCs and MPCs might contribute to AML progression, since Sipa1 loss could induce BM niche alterations, causing myeloproliferative neoplasms. 31 In summary, our findings provide new evidence for MLL-AF9 AML-induced dynamic niche alterations and the temporal roles of BM MSPCs during the development of AML. BM native Ebf2 1 cells suppress AML onset and progression.…”

Section: Discussionmentioning

confidence: 59%

“…and Runx2 remained unaltered, while the late-stage osteoblast marker Col1a1 and Bglap (osteocalcin) decreased in AML MSPCs, indicating a possible osteoblast maturation block in AML. Interestingly, Sipa1, whose expression in the BM niche is critical for maintaining normal hematopoiesis, 31 was significantly decreased in AML MSCs and MPCs ( Figure 4A-B).…”

Section: Dynamic Molecular Alteration Of Bm Cellular Niches In Aml Micementioning

confidence: 99%

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Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

et al. 2018

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Despite increasing evidence for the involvement of bone marrow (BM) hematopoietic stem cell niche in leukemogenesis, how BM mesenchymal stem and progenitor cells (MSPCs) contribute to leukemia niche formation and progression remains unclear. Using an MLL-AF9 acute myeloid leukemia (AML) mouse model, we demonstrate dynamic alterations of BM cellular niche components, including MSPCs and endothelial cells during AML development and its association with AML engraftment. Primary patient AML cells also induced similar niche alterations in xenografted mice. AML cell infiltration in BM causes an expansion of early B-cell factor 2 (Ebf2) MSPCs with reduced expression and enhanced generation of more differentiated mesenchymal progenitor cells. Importantly, in vivo fate-mapping indicates that Ebf2 MSPCs participated in AML niche formation. Ebf2 cell deletion accelerated the AML development. These data suggest that native BM MSPCs may suppress AML. However, they can be remodeled by AML cells to form leukemic niche that might contribute to AML progression. AML induced dysregulation of hematopoietic niche factors like ,, ,, , and in AML BM MSPCs, which was associated with AML engraftment and partially appeared before the massive expansion of AML cells, indicating the possible involvement of the niche factors in AML progression. Our study demonstrates distinct dynamic features and roles of BM MSPCs during AML development.

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Section: Discussionmentioning

confidence: 59%

Section: Dynamic Molecular Alteration Of Bm Cellular Niches In Aml Micementioning

confidence: 99%

Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

et al. 2018

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“…Rap1 is a molecular switch of the Ras family that regulates cell signaling through diverse cellular receptors; it is activated to a GTP form by specific GEF linked to various receptors, whereas it is swiftly inactivated to a GDP form by GAP, represented by C3G and Sipa1, respectively . Although C3G is expressed rather ubiquitously in many tissues, Sipa1 is predominantly expressed in hematopoietic tissues, including both hematopoietic cells and stroma cells . We previously reported that Sipa1‐ deficient mice develop quite diverse late‐onset hematopoietic disorders, ranging from pancytopenia resembling MDS to overt MPN .…”

Section: Introductionmentioning

confidence: 99%

“…17 As wild-type BMC also developed MDS/MPN of late onset in Sipa1 −/− recipients, the overall effects in Sipa1-deficiency were, in part, attributed to dysregulated niche cell function. 15 Thus, involvement of Rap1 signaling in regulating HSPC per se remains to be verified.…”

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confidence: 99%

“…12,13 Although C3G is expressed rather ubiquitously in many tissues, Sipa1 is predominantly expressed in hematopoietic tissues, including both hematopoietic cells 12 and stroma cells. 14,15 We previously reported that Sipa1-deficient mice develop quite diverse late-onset hematopoietic disorders, ranging from pancytopenia resembling MDS to overt MPN. 16 We also reported that BM HSPC in Sipa1 −/− mice tended to be decreased with increased genetic stress preceding overt hematopoietic disorders.…”

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confidence: 99%

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Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long‐term hematopoiesis

et al. 2019

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Adult long‐term hematopoiesis depends on sustaining hematopoietic stem/progenitor cells ( HSPC ) in bone marrow ( BM ) niches, where their balance of quiescence, self‐renewal, and hematopoietic differentiation is tightly regulated. Although various BM stroma cells that produce niche factors have been identified, regulation of the intrinsic responsiveness of HSPC to the niche factors remains elusive. We previously reported that mice deficient for Sipa1 , a Rap1 GTP ase‐activating protein, develop diverse hematopoietic disorders of late onset. Here we showed that transplantation of BM cells expressing membrane‐targeted C3G (C3G‐F) , a Rap1 GTP / GDP exchanger, resulted in the progressive decline of the numbers of HSPC repopulated in BM with time and impaired long‐term hematopoiesis of all cell lineages. C3G‐F / HSPC were sustained for months in spleen retaining hematopoietic potential, but these cells inefficiently contributed to overall hematopoietic reconstitution. C3G‐F / HSPC showed enhanced proliferation and differentiation with accelerated progenitor cell exhaustion in response to stem cell factor ( SCF ). Using a Ba/F3 cell line, we confirmed that the increased basal Rap1 GTP levels with C3G‐F expression caused a markedly prolonged activation of c‐Kit receptor and downstream signaling through SCF ligation. A minor population of C3G‐F / HSPC also showed enhanced proliferation in the presence of thrombopoietin ( TPO ) compared to Vect / HSPC . Current results suggest an important role of basal Rap1 activation status of HSPC in their maintenance in BM for sustaining long‐term adult hematopoiesis.

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MDS Stem Cell Biology

Villaume

Ferrell

Savona

2020

Diagnosis and Management of Myelodysplastic Syndromes

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Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

Cited by 32 publications

References 61 publications

Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long‐term hematopoiesis

MDS Stem Cell Biology

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