IP3 3-kinase B prevents bone marrow failure

Rigaud, Stéphanie; Sauer, Karsten

doi:10.18632/oncotarget.4480

Cited by 2 publications

(13 citation statements)

References 7 publications

(26 reference statements)

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“…Persistent activation reduces HSC life span and pluripotency. This can cause immunodeficiencies, anemia, hematopoietic failure, blood cancer, and death ( 30 ).…”

Section: Non-canonical Antagonism By Ip 4 Preventsmentioning

confidence: 99%

“…A key mediator of HSC activation that needs to be inactivated for re-entry into quiescence is PI3K signaling via Akt and downstream mammalian or mechanistic target of rapamycin (mTOR). In addition, we have identified Itpkb as a promoter of HSC quiescence and homeostasis that acts at least in part by inactivating Akt in HSC ( 26 , 30 ).…”

Section: Non-canonical Antagonism By Ip 4 Preventsmentioning

confidence: 99%

“…Upon resolution of the stress, PI3K inactivation is required for HSC re-entry into quiescence. Excessive PI3K/Akt activity transiently expands HSC, followed by depletion and reduced long-term repopulating capability associated with variable myeloproliferative disease, T-cell acute lymphoblastic (T-ALL) or acute myeloblastic (AML) leukemia ( 30 ). Thus, PI3K/Akt activity in HSC needs to be tuned into an appropriate window.…”

Section: Non-canonical Antagonism By Ip 4 Preventsmentioning

confidence: 99%

“… Phosphoinositide 3-kinase (PI3K) loss-of-function or gain-of-function affects multiple stages of hematopoietic development, and mature hematopoietic cells. Hematopoiesis originates from quiescent, long-lived, and pluripotent hematopoietic stem cells (HSC) which reside in BM (BM) niches with low-metabolic and cell cycle activity ( 26 , 30 ). After occasional division and activation, HSC daughter cells can differentiate through multiple hematopoietic progenitor cell stages including multipotent progenitors (MPP) into lymphoid or myeloid lineages.…”

Section: Introductionmentioning

confidence: 99%

“…CMP can also generate common DC precursors, which in turn generate most DC subsets ( 31 ). The map indicates major hematopoietic progenitors and mature cell types that are negatively (red font) or positively (green font) affected in mice deficient for the indicated PI3K isoforms, SHIP-1 , or PTEN ( 4 – 9 , 26 , 30 – 34 ). Mixed red–green font indicates complex phenotypes with activation and inactivation components.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides

Elich

Sauer

2018

Front. Immunol.

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One of the most paramount receptor-induced signal transduction mechanisms in hematopoietic cells is production of the lipid second messenger phosphatidylinositol(3,4,5)trisphosphate (PIP3) by class I phosphoinositide 3 kinases (PI3K). Defective PIP3 signaling impairs almost every aspect of hematopoiesis, including T cell development and function. Limiting PIP3 signaling is particularly important, because excessive PIP3 function in lymphocytes can transform them and cause blood cancers. Here, we review the key functions of PIP3 and related phosphoinositides in hematopoietic cells, with a special focus on those mechanisms dampening PIP3 production, turnover, or function. Recent studies have shown that beyond “canonical” turnover by the PIP3 phosphatases and tumor suppressors phosphatase and tensin homolog (PTEN) and SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1/2), PIP3 function in hematopoietic cells can also be dampened through antagonism with the soluble PIP3 analogs inositol(1,3,4,5)tetrakisphosphate (IP4) and inositol-heptakisphosphate (IP7). Other evidence suggests that IP4 can promote PIP3 function in thymocytes. Moreover, IP4 or the kinases producing it limit store-operated Ca2+ entry through Orai channels in B cells, T cells, and neutrophils to control cell survival and function. We discuss current models for how soluble inositol phosphates can have such diverse functions and can govern as distinct processes as hematopoietic stem cell homeostasis, neutrophil macrophage and NK cell function, and development and function of B cells and T cells. Finally, we will review the pathological consequences of dysregulated IP4 activity in immune cells and highlight contributions of impaired inositol phosphate functions in disorders such as Kawasaki disease, common variable immunodeficiency, or blood cancer.

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“…Persistent activation reduces HSC life span and pluripotency. This can cause immunodeficiencies, anemia, hematopoietic failure, blood cancer, and death ( 30 ).…”

Section: Non-canonical Antagonism By Ip 4 Preventsmentioning

confidence: 99%

Section: Non-canonical Antagonism By Ip 4 Preventsmentioning

confidence: 99%

Section: Non-canonical Antagonism By Ip 4 Preventsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides

Elich

Sauer

2018

Front. Immunol.

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Regulation of Hematopoietic Stem Cell Fate and Malignancy

Cho

Lee

Yoon

et al. 2020

IJMS

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The regulation of hematopoietic stem cell (HSC) fate decision, whether they keep quiescence, self-renew, or differentiate into blood lineage cells, is critical for maintaining the immune system throughout one’s lifetime. As HSCs are exposed to age-related stress, they gradually lose their self-renewal and regenerative capacity. Recently, many reports have implicated signaling pathways in the regulation of HSC fate determination and malignancies under aging stress or pathophysiological conditions. In this review, we focus on the current understanding of signaling pathways that regulate HSC fate including quiescence, self-renewal, and differentiation during aging, and additionally introduce pharmacological approaches to rescue defects of HSC fate determination or hematopoietic malignancies by kinase signaling pathways.

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IP3 3-kinase B prevents bone marrow failure

Cited by 2 publications

References 7 publications

Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides

Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides

Regulation of Hematopoietic Stem Cell Fate and Malignancy

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