IP3 3-kinase B prevents bone marrow failure

The Greek philosopher Plato emphasized the importance of moderating personal desires for the functioning of society. The virtue of moderation is also critical for the live-long function of hematopoietic stem cells (HSC), the origin of all blood cells. To prevent undue activation, which can deplete HSC and increase the risk of blood cancer, HSC need to restrain signaling by phosphoinositide 3-kinases (PI3K) a pivotal pathway whose hyperactivation contributes to many diseases [1]. Yet, the precise mechanisms limiting PI3K-signaling within HSC remain ill understood. We recently presented evidence that they include non-canonical PI3K-regulation by the little-studied enzyme inositoltrisphosphate 3-kinase B (IP3 3-kinase B/Itpkb) in HSC [2]. Itpkb -/mice died with HSC/hematopoietic-progenitor-cell (HPC) depletion and anemia. Thus, we speculate that defective PI3Kdampening by Itpkb or other moderators contributes to the frequent HSC-defects in bone marrow (BM) failure syndromes [3]. HSC are pluripotent and long-lived. Their longevity relies on their relative metabolic quiescence and only rare division for self-renewal. This dormancy is facilitated by HSC-residence in hypoxic BM niches. Metabolic adaptation and interactions with niche adhesionmolecules and cyto-/chemokines including stem-cellfactor (SCF) keep HSC quiescent and self-renewing [2, 4]. Hematopoietic stress causes the release of cytokines or other factors which mobilize and activate HSC to proliferate and generate shorter-lived HPC. These give rise to the different blood cell lineages. Once blood cell homeostasis is re-established, HSC re-enter dormancy. This is critical, because continuous HSC-activation reduces self-renewal and ultimately depletes HSC, causing BM failure and immunodeficiencies, and promoting certain blood cancers [1, 2, 4]. Increasing evidence suggests that signaling from cytokines like SCF in dormant HSC must be tuned into an intensity-range that ensures self-renewal, but avoids activation. The underlying mechanisms are incompletely understood [1, 2]. Activated by cytokines and other signals, PI3K and its effectors Akt and mTORC1 are required for HSC self-renewal and function. But excessive PI3K/Akt activity transiently expands HSC, followed by depletion and reduced long-term engraftment associated with variable myeloproliferative disease, T-cellacute-lymphoblastic (T-ALL) or acute-myeloblasticleukemia (AML) [1, 2]. PI3K produce the membranelipid phosphatidylinositol(3,4,5)trisphosphate (PIP3), a recruiting and activating ligand for Akt and other effectors. To prevent excessive PI3K-signaling, PIP3-levels in many cell types are limited through its removal by the lipidphosphatases PTEN and SHIP (references in [1, 2]). But the relative importance of HSC inversus extrinsic PTEN functions remains controversial, and SHIP-1 may primarily control HSC-homeostasis cell-extrinsically (references in [2]). Could there be another HSC-intrinsic PI3K-moderator? Itpkb phosphorylates the Ca2+-mobilizing secondmessenger IP3 into inositol(1,3,4,5)tetrakisphosphate (IP4). We and others have identified receptor-induced IP4 production by Itpkb as essential for signaling in lymphocytes, granulocyte-monocyte-progenitors (GMP) and neutrophils (references in [2, 5]). IP4 is identical with the protein-binding moiety of PIP3. In NK cells, GMP and neutrophils, IP4 competitively limits PIP3-binding to and activation of Akt (references in [2]). ItpkB is expressed in HSC. To thus determine if IP4/PIP3-antagonism moderates PI3K-signaling in HSC, we studied Itpkb-/mice. Young Itpkb-/mice accumulated phenotypic HSC which were less quiescent and proliferated more than Itpkb+/+ controls [2]. Transcriptome-analyses showed downregulation of stemnessand quiescence-associated, but upregulation of activationand differentiation-associated genes in Itpkb-/vs. wt HSC. Itpkb-/HSC showed intact BM-homing, but Editorial