PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events

Author(s):Show less -

Mendes, Rui D. ^[1] ; Sarmento, Leonor M. ^[2] ; Cante-Barrett, Kirsten ^[1] ; Zuurbier, Linda ^[1] ; Buijs-Gladdines, Jessica G. C. A. M. ^[1] ; Povoa, Vanda ^[2] ; Smits, Willem K. ^[1] ; Abecasis, Miguel ^[3] ; Yunes, J. Andres ^[4] ; Sonneveld, Edwin ^[5] ; Horstmann, Martin A. ^{[6, 7]} ; Pieters, Rob ^[1] ; Barata, Joao T. ^[2] ; Meijerink, Jules P. P. ^[1]

Affiliation

^[1] Erasmus MC, Dept Pediat Oncol Hematol, Sophia Childrens Hosp, Rotterdam - Netherlands

^[2] Univ Lisbon, Fac Med, Inst Med Mol, Lisbon - Portugal

^[3] Hosp Sta Cruz, Cardiol Pediat Med Cirurg, Lisbon - Portugal

^[4] Ctr Infantil Boldrini, Sao Paulo - Brazil

^[5] Dutch Childhood Oncol Grp, The Hague - Netherlands

^[6] German Cooperat Study Grp Childhood Acute Lymphob, Hamburg - Germany

^[7] Univ Med Ctr Hamburg Eppendorf, Clin Pediat Hematol & Oncol, Res Inst Childrens Canc Ctr Hamburg, Hamburg - Germany

• Document type: Journal article
• Source: Blood; v. 124, n. 4, p. 567-578, JUL 24 2014.
• Web of Science Citations: 38

Abstract

Phosphatase and tensin homolog (PTEN)-inactivating mutations and/or deletions are an independent risk factor for relapse of T-cell acute lymphoblastic leukemia (T-ALL) patients treated on Dutch Childhood Oncology Group or German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia protocols. Some monoallelic mutated or PTEN wild-type patients lack PTEN protein, implying that additional PTEN inactivation mechanisms exist. We show that PTEN is inactivated by small deletions affecting a few exons in 8% of pediatric T-ALL patients. These microdeletions were clonal in 3% and subclonal in 5% of patients. Conserved deletion breakpoints are flanked by cryptic recombination signal sequences (cRSSs) and frequently have non-template-derived nucleotides inserted in between breakpoints, pointing to an illegitimate RAG recombination-driven activity. Identified cRSSs drive RAG-dependent recombination in a reporter system as efficiently as bona fide RSSs that flank gene segments of the T-cell receptor locus. Remarkably, equivalent microdeletions were detected in thymocytes of healthy individuals. Microdeletions strongly associate with the TALLMO subtype characterized by TAL1 or LMO2 rearrangements. Primary and secondary xenotransplantation of TAL1-rearranged leukemia allowed development of leukemic subclones with newly acquired PTEN microdeletions. Ongoing RAG activity may therefore actively contribute to the acquisition of preleukemic hits, clonal diversification, and disease progression. (AU)

• FAPESP's process: 08/10034-1 - Bone marrow microenvironment and PI3K pathway in resistance to chemotherapy of pediatric acute lymphoblastic leukemia
• Grantee: José Andrés Yunes
• Support Opportunities: Regular Research Grants