Hematopoietic Stem Cell Activity Is Regulated by Pten Phosphorylation Through a Niche-Dependent Mechanism

Abstract

The phosphorylated form of Pten (p-Pten) is highly expressed in >70% of acute myeloid leukemia samples. However, the role of p-Pten in normal and abnormal hematopoiesis has not been studied. We found that Pten protein levels are comparable among long-term (LT) hematopoietic stem cells (HSCs), short-term (ST) HSCs, and multipotent progenitors (MPPs); however, the levels of p-Pten are elevated during the HSC-to-MPP transition. To study whether p-Pten is involved in regulating self-renewal and differentiation in HSCs, we compared the effects of overexpression of p-Pten and nonphosphorylated Pten (non-p-Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs. We found that overexpression of non-p-Pten enhances the LT-HRC of HSCs, whereas overexpression of p-Pten promotes myeloid differentiation and compromises the LT-HRC of HSCs. Such phosphorylation-regulated Pten functioning is mediated by repressing the cell:cell contact-induced activation of Fak/p38 signaling independent of Pten's lipid phosphatase activity because both p-Pten and non-p-Pten have comparable activity in repressing PI3K/Akt signaling. Our studies suggest that, in addition to repressing PI3K/Akt/mTor signaling, non-pPten maintains HSCs in bone marrow niches via a cell-contact inhibitory mechanism by inhibiting Fak/p38 signaling-mediated proliferation and differentiation. In contrast, p-Pten promotes the proliferation and differentiation of HSCs by enhancing the cell contact-dependent activation of Src/Fak/p38 signaling. STEM CELLS 2016;34:2130-2144 SIGNIFICANCE STATEMENTOur studies presented in this manuscript suggest that in addition to inhibiting the PI3K/Akt/ mTor pathway, Pten maintains the undifferentiated quiescent state of HSCs in the bone marrow niche by an additional mechanism, namely a cell:cell contact inhibiting mechanism accomplished by repressing niche-stimulated Fak and p38 signaling. The cell:cell contact inhibitory function of Pten is regulated by phosphorylation of its c-terminal tail. Inhibition of such phosphorylation might help to maintain HSCs in vivo.

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…Apart from the iconic BCR/ABL oncogene formation in chronic myeloid leukemia (CML) and the genetic abnormalities frequently linked to treatment resistance and poor patient outcome in acute myeloid leukemia (AML), for example the unique PML-RARA fusion in acute promyelocytic leukaemia (APL; AML M3), the PI3K/AKT pathway can function as a prosurvival factor in leukemia stem cells and early committed leukemic precursors with the following facts: Firstly, the overall genetic alterations of PIK3CA (0.6%), PIK3R1 (0.6%), PIK3R2 (0.4%), AKT1 (0.5%), AKT2 (0.1%) and PTEN (0.7%, Table 1) are observed in leukemia (Table 1). Secondly, PTEN plays critical roles in regulating not only hematopoietic stem cell activity through a Niche-dependent mechanism, but also hematopoiesis and leukemogenesis [341][342][343]. Furthermore, TAL1, c-Jun, EZH2, TRIM22, ETV6/RUNX1, miR-7, -22, -26b, -103, -125b, -126, -139-5p, -181c, -193a, -628, and -3142, as well as LncRNA HULC, UCA1, linc00239 and LINC00265 control leukemogenesis, proliferation, apoptosis or chemoresistance via PI3K/AKT pathway [344][345][346][347][348][349][350][351][352][353][354][355][356][357][358][359][360][361][362][363].…”

Signaling Pathways in Leukemic Stem Cells

“…Moreover, unphosphorylated PTEN restricts HSCs to a quiescent state in the bone marrow niche by dual inhibition of PI3K/AKT and SRC signaling. In contrast, p-PTEN represses PI3K/AKT, but promotes the niche contact-stimulated signaling that regulates the proliferation and lodging of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow niche, whereas unphosphorylated PTEN represses both types of signaling (69). Thus, this study highlights the dual cell-autonomous and non-cell autonomous regulation of HSCs by PTEN.…”

“…In another study, Li et al showed that PTEN protein levels are similar among different HSC populations and multipotent progenitors (MPPs), but that there is increased PTEN phosphorylation (p-PTEN) during the transition from long term-to short term-HSCs, and further to MPPs, where p-PTEN levels are inversely correlated with the self-renewal capacity and long term repopulation capacity of HSPCs (69). Serial transplantation experiments demonstrated that unphosphorylated PTEN augments the self-renewal of wild type long-term repopulating cells, and promotes myeloid over lymphoid differentiation.…”

The c-Myc/miR17-92/PTEN Axis Tunes PI3K Activity to Control Expression of Recombination Activating Genes in Early B Cell Development

“…The regulation of PI3K activity in HSCs is unknown. Studies indicate that multipotent HSCs depend on Dicer and miRNA biogenesis for persistence ( 58 ), and that PTEN expression regulates HSCs activity by repressing the PI3K/Akt/mTor signaling ( 59 ). It is possible that the c-Myc/miR17-92/PTEN axis may also function to regulate PI3K in HSCs.…”