Mutations of PHF6 Are Associated with Mutations of NOTCH1, JAK1 and Rearrangement of SET-NUP214 in T-cell Acute Lymphoblastic Leukemia

Overview

Journal Haematologica

Specialty Hematology

Date 2011 Sep 2

PMID 21880637

Citations 36

Authors

Qian Wang

Huiying Qiu

Hui Jiang

Lili Wu

Shasha Dong

Jinlan Pan

Wenjuan Wang

Nana Ping

Jing Xia

Aining Sun

Depei Wu

Yongquan Xue

Hans G Drexler

Roderick A F MacLeod

Suning Chen

Affiliations

Soon will be listed here.

Abstract

Background: Mutations in the PHF6 gene were recently described in patients with T-cell acute lymphoblastic leukemia and in those with acute myeloid leukemia. The present study was designed to determine the prevalence of PHF6 gene alterations in T-cell acute lymphoblastic leukemia.

Design And Methods: We analyzed the incidence and prognostic value of PHF6 mutations in 96 Chinese patients with T-cell acute lymphoblastic leukemia. PHF6 deletions were screened by real-time quantitative polymerase chain reaction and array-based comparative genomic hybridization. Patients were also investigated for NOTCH1, FBXW7, WT1, and JAK1 mutations together with CALM-AF10, SET-NUP214, and SIL-TAL1 gene rearrangements.

Results: PHF6 mutations were identified in 11/59 (18.6%) adult and 2/37 (5.4%) pediatric cases of T-cell acute lymphoblastic leukemia, these incidences being significantly lower than those recently reported. Although PHF6 is X-linked and mutations have been reported to occur almost exclusively in male patients, we found no sex difference in the incidences of PHF6 mutations in Chinese patients with T-cell acute lymphoblastic leukemia. PHF6 deletions were detected in 2/79 (2.5%) patients analyzed. NOTCH1 mutations, FBXW7 mutations, WT1 mutations, JAK1 mutations, SIL-TAL1 fusions, SET-NUP214 fusions and CALM-AF10 fusions were present in 44/96 (45.8%), 9/96 (9.4%), 4/96 (4.1%), 3/49 (6.1%), 9/48 (18.8%), 3/48 (6.3%) and 0/48 (0%) of patients, respectively. The molecular genetic markers most frequently associated with PHF6 mutations were NOTCH1 mutations (P=0.003), SET-NUP214 rearrangements (P=0.002), and JAK1 mutations (P=0.005). No differences in disease-free survival and overall survival between T-cell acute lymphoblastic leukemia patients with and without PHF6 mutations were observed in a short-term follow-up.

Conclusions: Overall, these results indicate that, in T-cell acute lymphoblastic leukemia, PHF6 mutations are a recurrent genetic abnormality associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214.

Citing Articles

Comprehensive genomic characterization of hematologic malignancies at a pediatric tertiary care center.

Kebede A, Garfinkle E, Mathew M, Varga E, Colace S, Wheeler G Front Oncol. 2024; 14:1498409.

PMID: 39687881 PMC: 11647012. DOI: 10.3389/fonc.2024.1498409.

Investigating the physiological role of S199A and S199D mutants of PHF6 protein in T-cell acute lymphoblastic leukemia.

Erdogan G, Ozes O, Kupesiz A, Yoldas S Turk J Med Sci. 2024; 53(5):1234-1243.

PMID: 38812997 PMC: 10763810. DOI: 10.55730/1300-0144.5689.

Integrated analysis of transcriptome and genome variations in pediatric T cell acute lymphoblastic leukemia: data from north Indian tertiary care center.

Singh M, Sharma P, Bhatia P, Trehan A, Thakur R, Sreedharanunni S BMC Cancer. 2024; 24(1):325.

PMID: 38459434 PMC: 10924344. DOI: 10.1186/s12885-024-12063-6.

Rearrangements in Leukemia Patients: A Case Series From a Single Institution.

Choi Y, Min Y, Lee S, Choi J, Shin S Ann Lab Med. 2023; 44(4):335-342.

PMID: 38145892 PMC: 10961622. DOI: 10.3343/alm.2023.0301.

SET-CAN/NUP214 fusion gene in leukemia: general features and clinical advances.

Song J, Li H, Fan S Front Oncol. 2023; 13:1269531.

PMID: 37909026 PMC: 10613893. DOI: 10.3389/fonc.2023.1269531.

References

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

Zhu Y, Zhao W, Fu J, Shi J, Pan Q, Hu J . NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis. Clin Cancer Res. 2006; 12(10):3043-9. DOI: 10.1158/1078-0432.CCR-05-2832. View

Lower K, Turner G, Kerr B, Mathews K, Shaw M, Gedeon A . Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome. Nat Genet. 2002; 32(4):661-5. DOI: 10.1038/ng1040. View

Gutierrez A, Sanda T, Ma W, Zhang J, Grebliunaite R, Dahlberg S . Inactivation of LEF1 in T-cell acute lymphoblastic leukemia. Blood. 2010; 115(14):2845-51. PMC: 2854430. DOI: 10.1182/blood-2009-07-234377. View

Thompson B, Buonamici S, Sulis M, Palomero T, Vilimas T, Basso G . The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med. 2007; 204(8):1825-35. PMC: 2118676. DOI: 10.1084/jem.20070872. View

Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L . Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med. 2008; 205(4):751-8. PMC: 2292215. DOI: 10.1084/jem.20072182. View

Paietta E, Ferrando A, Neuberg D, Bennett J, Racevskis J, Lazarus H . Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood. 2004; 104(2):558-60. DOI: 10.1182/blood-2004-01-0168. View

Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat C, Balbin M . PHF6 mutations in adult acute myeloid leukemia. Leukemia. 2010; 25(1):130-4. PMC: 3878659. DOI: 10.1038/leu.2010.247. View

Kox C, Zimmermann M, Stanulla M, Leible S, Schrappe M, Ludwig W . The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function. Leukemia. 2010; 24(12):2005-13. PMC: 3035973. DOI: 10.1038/leu.2010.203. View

10.

Kawamura M, Ohnishi H, Guo S, Sheng X, Minegishi M, Hanada R . Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia. Leuk Res. 1999; 23(2):115-26. DOI: 10.1016/s0145-2126(98)00146-5. View

11.

Uckun F, Gaynon P, Sensel M, Nachman J, Trigg M, Steinherz P . Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study. J Clin Oncol. 1997; 15(6):2214-21. DOI: 10.1200/JCO.1997.15.6.2214. View

12.

Chao M, Todd M, Kontny U, Neas K, Sullivan M, Hunter A . T-cell acute lymphoblastic leukemia in association with Börjeson-Forssman-Lehmann syndrome due to a mutation in PHF6. Pediatr Blood Cancer. 2010; 55(4):722-4. PMC: 2933084. DOI: 10.1002/pbc.22574. View

13.

Voss A, Gamble R, Collin C, Shoubridge C, Corbett M, Gecz J . Protein and gene expression analysis of Phf6, the gene mutated in the Börjeson-Forssman-Lehmann Syndrome of intellectual disability and obesity. Gene Expr Patterns. 2007; 7(8):858-71. DOI: 10.1016/j.modgep.2007.06.007. View

14.

Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G . NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia. 2010; 24(12):2023-31. DOI: 10.1038/leu.2010.205. View

15.

Malyukova A, Dohda T, von der Lehr N, Akhoondi S, Akhondi S, Corcoran M . The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res. 2007; 67(12):5611-6. DOI: 10.1158/0008-5472.CAN-06-4381. View

16.

Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela J, Dik W . The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood. 2007; 110(4):1251-61. DOI: 10.1182/blood-2006-12-064683. View

17.

Asnafi V, Radford-Weiss I, Dastugue N, Bayle C, Leboeuf D, Charrin C . CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage. Blood. 2003; 102(3):1000-6. DOI: 10.1182/blood-2002-09-2913. View

18.

Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N . PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet. 2010; 42(4):338-42. PMC: 2847364. DOI: 10.1038/ng.542. View

19.

Kleppe M, Lahortiga I, El Chaar T, De Keersmaecker K, Mentens N, Graux C . Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet. 2010; 42(6):530-5. PMC: 2957655. DOI: 10.1038/ng.587. View

20.

Zuurbier L, Homminga I, Calvert V, te Winkel M, Buijs-Gladdines J, Kooi C . NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols. Leukemia. 2010; 24(12):2014-22. DOI: 10.1038/leu.2010.204. View