Zuurbier Linda, Petricoin Emanuel F, Vuerhard Maartje J, Calvert Valerie, Kooi Clarissa, Buijs-Gladdines Jessica G C A M, Smits Willem K, Sonneveld Edwin, Veerman Anjo J P, Kamps Willem A, Horstmann Martin, Pieters Rob, Meijerink Jules P P
Department of Pediatric Oncology/Hematology, Erasmus MC Rotterdam-Sophia Children’s Hospital, Rotterdam, the Netherlands.
Haematologica. 2012 Sep;97(9):1405-13. doi: 10.3324/haematol.2011.059030. Epub 2012 Apr 4.
PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors.
The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols.
PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005).
PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors.
PI3K/AKT通路突变见于T细胞急性淋巴细胞白血病，但它们的总体影响以及与其他基因畸变的关联尚不清楚。PTEN突变被认为是继NOTCH1激活突变之后的二次突变，并导致细胞对γ-分泌酶抑制剂产生耐药性。
在接受DCOG或COALL方案治疗的、具有良好基因特征的儿科T细胞白血病患者队列（n = 146）中，研究了PTEN、PI3K和AKT畸变的影响。
分别在13%和2%的患者中检测到PTEN和AKT E17K畸变。在偶发病例中发现了PTEN剪接缺陷。存在无PTEN蛋白但缺乏外显子、剪接、启动子突变或启动子高甲基化的患者。PTEN/AKT突变在TAL或LMO重排的白血病中尤为常见，但在TLX3重排的患者中几乎不存在（P = 0.03），这与NOTCH1激活突变的情况相反。大多数PTEN/AKT突变患者要么缺乏NOTCH1激活突变（P = 0.006），要么具有较弱的NOTCH1激活突变（P = 0.011），因此细胞内NOTCH1、cMYC和MUSASHI水平较低。无PTEN/AKT和NOTCH1激活突变的T细胞白血病患者预后良好，复发累积发生率仅为8%，而PTEN/AKT和/或NOTCH1激活的患者为35%（P = 0.005）。
18%的儿科T细胞急性淋巴细胞白血病患者存在PI3K/AKT通路畸变。这些病例中缺乏强烈的NOTCH1激活突变可能解释了细胞对γ-分泌酶抑制剂的不敏感性。
