High Frequency of PTEN, PI3K, and AKT Abnormalities in T-cell Acute Lymphoblastic Leukemia

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2009 May 22

PMID 19458356

Citations 218

Authors

Alejandro Gutierrez

Takaomi Sanda

Ruta Grebliunaite

Arkaitz Carracedo

Leonardo Salmena

Yebin Ahn

Suzanne Dahlberg

Donna Neuberg

Lisa A Moreau

Stuart S Winter

Richard Larson

Jianhua Zhang

Alexei Protopopov

Lynda Chin

Pier Paolo Pandolfi

Lewis B Silverman

Stephen P Hunger

Stephen E Sallan

A Thomas Look

Affiliations

Soon will be listed here.

Abstract

To more comprehensively assess the pathogenic contribution of the PTEN-PI3K-AKT pathway to T-cell acute lymphoblastic leukemia (T-ALL), we examined diagnostic DNA samples from children with T-ALL using array comparative genomic hybridization and sequence analysis. Alterations of PTEN, PI3K, or AKT were identified in 47.7% of 44 cases. There was a striking clustering of PTEN mutations in exon 7 in 12 cases, all of which were predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed to induce remission in 3 of the 4 patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, compared with none of the 12 patients with mutations of PTEN exon 7 (P = .007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings add significant support to the rationale for the development of therapies targeting the PTEN-PI3K-AKT pathway in T-ALL.

Citing Articles

A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer.

Andrieu G, Simonin M, Cabannes-Hamy A, Lengline E, Marcais A, Theron A Nat Commun. 2025; 16(1):2191.

PMID: 40038309 PMC: 11880427. DOI: 10.1038/s41467-025-57225-7.

Hedgehog and PI3K/Akt/mTOR Signaling Pathways Involvement in Leukemic Malignancies: Crosstalk and Role in Cell Death.

Sicurella M, De Chiara M, Neri L Cells. 2025; 14(4).

PMID: 39996741 PMC: 11853774. DOI: 10.3390/cells14040269.

ATM-deficient murine thymic T-cell lymphoblastic lymphomas are PTEN-deficient and require AKT signaling for survival.

An J, Hathcock K, Steinberg S, Choo-Wosoba H, Hodes R PLoS One. 2024; 19(12):e0312864.

PMID: 39637056 PMC: 11620668. DOI: 10.1371/journal.pone.0312864.

BCAT1 is a NOTCH1 target and sustains the oncogenic function of NOTCH1.

Tosello V, Di Martino L, Papathanassiu A, Santa S, Pizzi M, Mussolin L Haematologica. 2024; 110(2):350-367.

PMID: 39234857 PMC: 11788623. DOI: 10.3324/haematol.2024.285552.

Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting OSBP.

Cigler M, Imrichova H, Frommelt F, Caramelle L, Depta L, Rukavina A Nat Chem Biol. 2024; 21(2):193-202.

PMID: 38907113 PMC: 11782089. DOI: 10.1038/s41589-024-01614-4.

References

ONeil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C . FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007; 204(8):1813-24. PMC: 2118656. DOI: 10.1084/jem.20070876. View

Bassan R, Gatta G, Tondini C, Willemze R . Adult acute lymphoblastic leukaemia. Crit Rev Oncol Hematol. 2004; 50(3):223-61. DOI: 10.1016/j.critrevonc.2003.11.003. View

Garcia-Echeverria C, Sellers W . Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008; 27(41):5511-26. DOI: 10.1038/onc.2008.246. View

Mullighan C, Goorha S, Radtke I, Miller C, Coustan-Smith E, Dalton J . Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007; 446(7137):758-64. DOI: 10.1038/nature05690. View

Gymnopoulos M, Elsliger M, Vogt P . Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci U S A. 2007; 104(13):5569-74. PMC: 1838453. DOI: 10.1073/pnas.0701005104. View

Tartaglia M, Martinelli S, Cazzaniga G, Cordeddu V, Iavarone I, Spinelli M . Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood. 2004; 104(2):307-13. DOI: 10.1182/blood-2003-11-3876. View

Graf Einsiedel H, von Stackelberg A, Hartmann R, Fengler R, Schrappe M, Janka-Schaub G . Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87. J Clin Oncol. 2005; 23(31):7942-50. DOI: 10.1200/JCO.2005.01.1031. View

Chow L, Baker S . PTEN function in normal and neoplastic growth. Cancer Lett. 2006; 241(2):184-96. DOI: 10.1016/j.canlet.2005.11.042. View

Kurose K, Gilley K, Matsumoto S, Watson P, Zhou X, Eng C . Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet. 2002; 32(3):355-7. DOI: 10.1038/ng1013. View

10.

. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008; 455(7216):1061-8. PMC: 2671642. DOI: 10.1038/nature07385. View

11.

Palomero T, Sulis M, Cortina M, Real P, Barnes K, Ciofani M . Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007; 13(10):1203-10. PMC: 2600418. DOI: 10.1038/nm1636. View

12.

Goldberg J, Silverman L, Levy D, Dalton V, Gelber R, Lehmann L . Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol. 2003; 21(19):3616-22. DOI: 10.1200/JCO.2003.10.116. View

13.

Bonneau D, Longy M . Mutations of the human PTEN gene. Hum Mutat. 2000; 16(2):109-22. DOI: 10.1002/1098-1004(200008)16:2<109::AID-HUMU3>3.0.CO;2-0. View

14.

Weng A, Ferrando A, Lee W, Morris 4th J, Silverman L, Sanchez-Irizarry C . Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004; 306(5694):269-71. DOI: 10.1126/science.1102160. View

15.

Winter S, Jiang Z, Khawaja H, Griffin T, Devidas M, Asselin B . Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2007; 110(5):1429-38. PMC: 1975833. DOI: 10.1182/blood-2006-12-059790. View

16.

Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S . High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004; 304(5670):554. DOI: 10.1126/science.1096502. View

17.

Perentesis J, Bhatia S, Boyle E, Shao Y, Ou Shu X, Steinbuch M . RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia. Leukemia. 2004; 18(4):685-92. DOI: 10.1038/sj.leu.2403272. View

18.

Liang D, Shih L, Fu J, Li H, Wang H, Hung I . K-Ras mutations and N-Ras mutations in childhood acute leukemias with or without mixed-lineage leukemia gene rearrangements. Cancer. 2006; 106(4):950-6. DOI: 10.1002/cncr.21687. View

19.

Maser R, Choudhury B, Campbell P, Feng B, Wong K, Protopopov A . Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature. 2007; 447(7147):966-71. PMC: 2714968. DOI: 10.1038/nature05886. View

20.

Carpten J, Faber A, Horn C, Donoho G, Briggs S, Robbins C . A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007; 448(7152):439-44. DOI: 10.1038/nature05933. View