Table 1:
HSC and LSC phenotypes resulting from genetic alterations in the PI3K pathway
| Gene | Alteration | Phenotype | Reference |
|---|---|---|---|
| Pik3r1 and Pik3r2 | KO | Decreased repopulating ability of fetal liver HSCs | Haneline et al 2006 |
| Akt | myr-AKT BMT model | Constitutively active AKT depletes HSCs and induces myeloproliferation, AML, and T-ALL | Kharas et al 2010 |
| Akt1/Akt2 | KO | Compound deletion of Akt1 and Akt2 impairs fetal HSC repopulation | Juntilla et al 2010 |
| Pik3ca | cKO (Mx1-Cre) | -no effect on HSC self-renewal G12D -increased survival in with KRAS JMML model |
Gritsman et al 2014 |
| Pten | cKO | -Pten deletion using Mx1-Cre perturbed HSC function, myeloproliferation, AML, and T-ALL when Pten is deleted in adult HSCs | Yilmaz et al 2006; Zhang et al 2006; Magee et al 2012 |
| -accelerated disease progression in CML model (using BCR-ABL-iCre retrovirus) | Peng et al 2010 | ||
| Pik3cp | cKO (Mx1-Cre) | p110p deletion prevents myeloproliferative neoplasia in context of Pten deletion and improves HSC function | Yuzugullu et al 2015 |
| Ship | KO | myeloproliferative phenotype, hypersensitivity to growth factors | Helgason et al 1998 |
| Pdk1 | cKO (Vav1-iCre) | -impaired repopulating potential and differentiation of fetal liver HSCs | Wang et al 2018 |
| cKO (Mx1-Cre) | -prolonged survival in MLL-AF9 AML model | Hu et al 2015 | |
| TSC1 | cKO (Mx1-Cre) | -increased HSC cycling and impaired self-renewal | Chen et al 2008 |
| mTOR | cKO(Mx1-Cre) | -loss of HSC quiescence | Guo et al 2013 |
| Rictor | cKO (Mx1-Cre/Vav1-iCre) | -no effect on HSC function -improved survival in Pten−/− model of leukemia |
Kalaitzidis et al 2012; Magee et al 2012 |
| Raptor | cKO (Mx1-Cre) | -impaired hematopoietic reconstitution -improved survival in Pten−/− model of leukemia |
Kalaitzidis et al 2012 |
| Foxo | KO or cKO (Mx1-Cre) | -increased HSC cycling, reduced repopulation activity, myeloproliferative phenotype, increased ROS levels | Tothova et al 2007;Yalcin et al 2010; Rimmele et al 2015; Liang et al 2016 |
| Foxo3a is important for maintenance of CML LICs | Naka et al 2010 | ||
| cKO (Mx1-Cre) | Foxo1/3/4 deletion induces differentiation of AML cells | Sykes et al 2011 | |
| S6K1 | KO | S6K1 KO impairs HSCs self-renewal and improves survival MLL-AF9 AML model | Ghosh et al 2016 |
| S6K1 KO causes defective repopulation of fetal liver HSCs | Shima et al 1998 |