Molecular Pathways in Childhood Acute Lymphoblastic Leukemia: From the Bench to the Bedside

Abstract

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, originating from a neoplastic deviation of B or T lymphocyte. Cytogenetic, cytofluorimetric, and genomic analyses clearly defined several subtypes of ALL. However, the leukemogenic process is characterized by different pathways' alteration which are still to be determined, in the attempt to identify specific targets to be druggable. In this review, we explore the main molecular pathways, which are commonly shared between different subtypes of pediatric ALL. These cell-signaling pathways affect many functions, including cell proliferation, apoptosis, migration, and differentiation. The PI3K/AKT/mTOR pathway is one of the most studied, with higher expected promises of being targetable. RAS pathway is also widely studied in all types of cancer. The Wnt/Beta catenin has been recently studied in ALL. Finally, CXCL12/CXCL4 axis has a crucial role in regulating hematopoietic stem cell and bone marrow niche. The complete characterization of these pathways will allow us to design a specific patient–disease profile associated with a tailored treatment, with the highest grade of efficacy and the lowest grade of toxicity.

Keywords

RAS - PI3K/AKT/mTOR - Wnt-Beta catenin - CXCL12 - childhood - ALL

• References

• 1 Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 2004; 9 (6) 667-676
• 2 Paez J, Sellers WR. PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling. Cancer Treat Res 2003; 115: 145-167
• 3 Morishita N, Tsukahara H, Chayama K , et al. Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia. Pediatr Blood Cancer 2012; 59 (1) 83-89
• 4 Roberts KG, Morin RD, Zhang J , et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 2012; 22 (2) 153-166
• 5 Gomes AM, Soares MV, Ribeiro P , et al. Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels. Haematologica 2014; 99 (6) 1062-1068
• 6 Palomero T, Sulis ML, Cortina M , et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007; 13 (10) 1203-1210
• 7 Gutierrez A, Sanda T, Grebliunaite R , et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009; 114 (3) 647-650
• 8 Bandapalli OR, Zimmermann M, Kox C , et al. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia. Haematologica 2013; 98 (6) 928-936
• 9 Zhang J, Grindley JC, Yin T , et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006; 441 (7092) 518-522
• 10 Hu L, Zaloudek C, Mills GB, Gray J, Jaffe RB. In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). Clin Cancer Res 2000; 6 (3) 880-886
• 11 Schultz RM, Merriman RL, Andis SL , et al. In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res 1995; 15 (4) 1135-1139
• 12 Subramaniam PS, Whye DW, Efimenko E , et al. Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell 2012; 21 (4) 459-472
• 13 Huang X, Proctor J, Yang Y , et al. The potent PI3K-δ,γ inhibitor, IPI-145, exhibits preclinical activity in murine and human T-cell acute lymphoblastic leukemia. Blood 2013; 122 (21) 1438
• 14 Gojo I, Perl A, Luger S , et al. Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome. Invest New Drugs 2013; 31 (5) 1217-1227
• 15 Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975; 28 (10) 721-726
• 16 Medvetz D, Priolo C, Henske EP. Therapeutic targeting of cellular metabolism in cells with hyperactive mTORC1: a paradigm shift. Mol Cancer Res 2015; 13 (1) 3-8
• 17 Bertacchini J, Guida M, Accordi B , et al. Feedbacks and adaptive capabilities of the PI3K/Akt/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis. Leukemia 2014; 28 (11) 2197-2205
• 18 Feldman ME, Apsel B, Uotila A , et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009; 7 (2) e38
• 19 Knight T, Irving JA. Ras/Raf/MEK/ERK pathway activation in childhood acute lymphoblastic leukemia and its therapeutic targeting. Front Oncol 2014; 4: 160
• 20 Glomset JA, Farnsworth CC. Role of protein modification reactions in programming interactions between ras-related GTPases and cell membranes. Annu Rev Cell Biol 1994; 10: 181-205
• 21 Casey PJ, Seabra MC. Protein prenyltransferases. J Biol Chem 1996; 271 (10) 5289-5292
• 22 Akopyan TN, Couedel Y, Orlowski M, Fournie-Zaluski MC, Roques BP. Proteolytic processing of farnesylated peptides: assay and partial purification from pig brain membranes of an endopeptidase which has the characteristics of E.C. 3.4.24.15. Biochem Biophys Res Commun 1994; 198 (2) 787-794
• 23 Gay B, Suarez S, Caravatti G, Furet P, Meyer T, Schoepfer J. Selective GRB2 SH2 inhibitors as anti-Ras therapy. Int J Cancer 1999; 83 (2) 235-241
• 24 Okan E, Drewett V, Shaw PE, Jones P. The small-GTPase RalA activates transcription of the urokinase plasminogen activator receptor (uPAR) gene via an AP1-dependent mechanism. Oncogene 2001; 20 (15) 1816-1824
• 25 Chang F, Steelman LS, Lee JT , et al. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 2003; 17 (7) 1263-1293
• 26 Chan IT, Kutok JL, Williams IR , et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J Clin Invest 2004; 113 (4) 528-538
• 27 Kolch W. Ras/Raf signalling and emerging pharmacotherapeutic targets. Expert Opin Pharmacother 2002; 3 (6) 709-718
• 28 Reuter CWM, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?. Blood 2000; 96 (5) 1655-1669
• 29 Araki T, Mohi MG, Ismat FA , et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med 2004; 10 (8) 849-857
• 30 Braun BS, Tuveson DA, Kong N , et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci U S A 2004; 101 (2) 597-602
• 31 Chan IT, Kutok JL, Williams IR , et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J Clin Invest 2004; 113 (4) 528-538
• 32 Le DT, Kong N, Zhu Y , et al. Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder. Blood 2004; 103 (11) 4243-4250
• 33 Li Q, Bohin N, Wen T , et al. Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness. Nature 2013; 504 (7478) 143-147
• 34 Tamai H, Miyake K, Takatori M , et al. Activated K-Ras protein accelerates human MLL/AF4-induced leukemo-lymphomogenicity in a transgenic mouse model. Leukemia 2011; 25 (5) 888-891
• 35 Fernández-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer 2011; 2 (3) 344-358
• 36 Castellano E, Downward J. RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2011; 2 (3) 261-274
• 37 Lunghi P, Tabilio A, Dall'Aglio PP , et al. Downmodulation of ERK activity inhibits the proliferation and induces the apoptosis of primary acute myelogenous leukemia blasts. Leukemia 2003; 17 (9) 1783-1793
• 38 Milella M, Estrov Z, Kornblau SM , et al. Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia. Blood 2002; 99 (9) 3461-3464
• 39 Yu C, Krystal G, Varticovksi L , et al. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Cancer Res 2002; 62 (1) 188-199
• 40 Wu J, Wong WW, Khosravi F, Minden MD, Penn LZ. Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Cancer Res 2004; 64 (18) 6461-6468
• 41 Weisberg E, Nonami A, Chen Z , et al. Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies. Leukemia 2015; 29 (1) 27-37
• 42 MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009; 17 (1) 9-26
• 43 Liu C, Li Y, Semenov M , et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 2002; 108 (6) 837-847
• 44 Gandhirajan RK, Staib PA, Minke K , et al. Small molecule inhibitors of Wnt/beta-catenin/lef-1 signaling induces apoptosis in chronic lymphocytic leukemia cells in vitro and in vivo. Neoplasia 2010; 12 (4) 326-335
• 45 Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20: 781-810
• 46 Seke Etet PF, Vecchio L, Bogne Kamga P, Nchiwan Nukenine E, Krampera M, Nwabo Kamdje AH ; SekeEtet PF. Normal hematopoiesis and hematologic malignancies: role of canonical Wnt signaling pathway and stromal microenvironment. Biochim Biophys Acta 2013; 1835 (1) 1-10
• 47 McWhirter JR, Neuteboom ST, Wancewicz EV, Monia BP, Downing JR, Murre C. Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia. Proc Natl Acad Sci U S A 1999; 96 (20) 11464-11469
• 48 Chiou SS, Wang LT, Huang SB , et al. Wntless (GPR177) expression correlates with poor prognosis in B-cell precursor acute lymphoblastic leukemia via Wnt signaling. Carcinogenesis 2014; 35 (10) 2357-2364
• 49 Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 2005; 434 (7035) 843-850
• 50 Leung JY, Kolligs FT, Wu R , et al. Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. J Biol Chem 2002; 277 (24) 21657-21665
• 51 Kaveri D, Kastner P, Dembélé D, Nerlov C, Chan S, Kirstetter P. β-Catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL. Blood 2013; 122 (5) 694-704
• 52 Zuurbier L, Petricoin III EF, Vuerhard MJ , et al. The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia. Haematologica 2012; 97 (9) 1405-1413
• 53 Bonnet M, Loosveld M, Montpellier B , et al. Posttranscriptional deregulation of MYC via PTEN constitutes a major alternative pathway of MYC activation in T-cell acute lymphoblastic leukemia. Blood 2011; 117 (24) 6650-6659
• 54 Gang EJ, Hsieh YT, Pham J , et al. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 2014; 33 (17) 2169-2178
• 55 Yang Y, Mallampati S, Sun B , et al. Wnt pathway contributes to the protection by bone marrow stromal cells of acute lymphoblastic leukemia cells and is a potential therapeutic target. Cancer Lett 2013; 333 (1) 9-17
• 56 Bhatla T, Wang J, Morrison DJ , et al. Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood 2012; 119 (22) 5201-5210
• 57 Dandekar S, Romanos-Sirakis E, Pais F , et al. Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia. Br J Haematol 2014; 167 (1) 87-99
• 58 Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res 2010; 16 (11) 2927-2931
• 59 Chiarini F, Lonetti A, Evangelisti C , et al. Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting. Biochim Biophys Acta 2016; 1863 (3) 449-463
• 60 de Lourdes Perim A, Amarante MK, Guembarovski RL, de Oliveira CE, Watanabe MA. CXCL12/CXCR4 axis in the pathogenesis of acute lymphoblastic leukemia (ALL): a possible therapeutic target. Cell Mol Life Sci 2015; 72 (9) 1715-1723
• 61 Allegretti M, Ricciardi MR, Licchetta R , et al. The pan-class I phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia. Sci Rep 2015; 5: 18137
• 62 Lonetti A, Antunes IL, Chiarini F , et al. Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia. Leukemia 2014; 28: 1196-1206
• 63 Daver N, Kantarjian HM, Thomas DA , et al. A Phase I/II Study Of Hyper-CVAD Plus Everolimus In Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Blood 2013; 122 (21) 3916
• 64 Park S, Chapuis N, Marcoux FS. A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia 2013; 27: 1479
• 65 Amadori S, Stasi R, Martelli AM , et al. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107). Br J Haematol 2015; 156 (2) 205-212