Blood malignancies are a heterogeneous group of neoplasms arising due to the disruption of normal hematopoiesis ^[1][2][1,2]. They are among the most common cancer types, accounting for 6.5% of all cancers around the world [3]. Hematologic malignancies are generally classified into leukemias, multiple myeloma (MM), non-Hodgkin lymphomas (NHLs), and Hodgkin lymphoma (HL) [4]. Each disease is characterized by different morphological features, prognosis, and treatment regimens [5]. 

The PI3K/Akt/mTOR pathway is one of the most important signaling pathways that regulates cell growth and proliferation. PI3K/Akt/mTOR activation is important for leukemogenesis and it is associated with an unfavorable prognosis. The pathway is apparently dysregulated in numerous human malignancies such as respiratory tumors, digestive system tumors, kidney cancer, skin cancer, breast, and ovarian cancer, to name a few ^[6][7][6,7]. The activation of the PI3K/Akt/mTOR axis has been detected in hematologic malignancies, including ALL, CLL, AML, and CML. PI3K/Akt/mTOR activation is important for leukemogenesis and it is associated with unfavorable prognosis. Inhibition of this pathway through specific inhibitors results in reduced leukemic cell proliferation ^[8][9][8,9]. In T-ALL, mutations and deletions leading to the phosphatase and tensin homolog (PTEN) loss are the most common reasons for the upregulation of the PI3K/Akt/mTOR signaling, as PTEN is a major negative regulator of this pathway. PTEN loss contributes to increased cell proliferation and chemoresistance in AML, ALL, and CML [10]. The PI3K/Akt/mTOR pathway is also known to play an important role in CLL, where it promotes autophagy and thus contributes to improved cell survival [11]. Moreover, the PI3K/Akt/mTOR axis is associated with several mutations in hematological malignancies. For instance, FLT3 mutations in AML promote proliferation through mTOR signaling, whereas BCR-ABL kinase in CML activates the PI3K/Akt/mTOR pathway by binding to the p85 PI3K regulatory subunit ^[11][12][11,12].

2. The PI3K/Akt/mTOR Signaling Pathway

PI3K is a lipid kinase family that phosphorylates inositol’s 3′-OH group in phospholipids on the plasma membrane [13]. Human cells contain three classes of PI3Ks. Class I PI3Ks consist of a catalytic isoform and a regulatory subunit which mediate the kinase activity. This class is divided into two subclasses—IA, activated by receptor tyrosine kinases (RTKs), and IB, activated by G protein-coupled receptors (GPCR) ^[14][15][14,15]. Genes PIK3CA, PIK3CB, and PI3KCD encode the class IA catalytic subunit isoforms p110α, p110β, and p110δ, respectively. These catalytic isoforms can form heterodimers with any of the regulating subunit isoforms, p85α, p55α or p50α (PIK3R1), p85β (PIK3R2), and p55γ (PIK3R3), all of which are p85α splicing variants. PIK3CG encodes the class IB p110γ catalytic subunit, which forms heterodimers with regulatory isoforms—p101 or p87, encoded, respectively, by PIK3R5 and PIK3R6. Interestingly, while p110α and p110β are ubiquitously expressed in all tissues, p110δ and p110γ expression seems to be highly restricted to leukocytes and the hematopoietic system ^{[14][16][17][18]}[14,16,17,18]. Class II PI3Ks contain only the catalytic subunit. This subunit has three isoforms—PI3K-C2α, PI3K-C2β, and PI3K-C2γ, encoded, respectively, by PIK3C2A, PIK3C2B, and PIK3C2G. Class III PI3Ks consist of Vps34 (vacuolar protein sorting 34), which is encoded by PIK3C3 ^[15][19][15,19] (Table 1). PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 is the second messenger that enables the interaction of phosphoinositide-dependent kinase 1 (PDK1) and Akt, resulting in Akt phosphorylation. Akt then promotes the phosphorylation of proteins responsible for enhancing cell growth, proliferation, and protein synthesis. Akt activity is maximal when it Is phosphorylated at both sites at Thr308 and Ser473 ^[15][20][15,20]. Tumor suppressors, such as phosphatase and tensin homolog (PTEN) and inositol polyphosphate 4-phosphatase type II (INPP4B), are involved in dephosphorylation of PIP3 to PIP2, therefore suppressing the activity of Akt and its downstream effectors. The Akt/protein kinase B (PKB) has three isoforms—Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ), all of which share similar structure and functions ^[21][22][21,22]. Once Akt is phosphorylated, it is able to promote protein synthesis and inhibit proapoptotic proteins such as BCL-2-antagonist of cell death (BAD), forkhead box protein O1 (FoxO1), BCL-2-like protein 11 (BIM), and pro-caspase-9. Akt activation also results in p53 degradation via phosphorylation of mouse double minute 2 homolog (MDM2) [23]. Akt can activate mTOR which is a serine/threonine protein kinase able to interact with different protein molecules by creating two complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [20]. mTORC1 function can be modulated by the PI3K/Akt pathway and rapamycin, whereas mTORC2 is sensitive to growth factors and insensitive to rapamycin, unless the exposure to rapamycin is prolonged ^[24][25][24,25]. Contrary to mTORC1, mTORC2 possesses the ability to regulate Akt activity upon PDK1 direct signal transduction [15]. It is worth mentioning that the mTORC1 signaling pathway is better characterized than mTORC2 [26]. Upon activation, mTORC1 stimulates cell growth and modulates protein synthesis by means of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), ribosomal protein S6 kinase 1 (p70S6K or S6K1), forkhead/winged helix box class O (FOXO) family, RAS/ERK, and many other pathways. On the other hand, mTORC2, by phosphorylating Akt, can control signaling of several growth factors ^[20][25][20,25]. Furthermore, phosphorylation of protein kinase C (PKC)δ, PKCζ, PCKγ, and PKCε by mTORC2 can also promote cytoskeleton construction [26] (Figure 1).