Mutations of PHF6 are associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214 in T-cell acute lymphoblastic leukemia - PubMed (original) (raw)

Clinical Trial

. 2011 Dec;96(12):1808-14.

doi: 10.3324/haematol.2011.043083. Epub 2011 Aug 31.

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

Clinical Trial

Mutations of PHF6 are associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214 in T-cell acute lymphoblastic leukemia

Qian Wang et al. Haematologica. 2011 Dec.

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.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

PHF6 mutations in T-ALL. (A) Structure of the PHF6 protein, including four nuclear localization signals (NLS) and two imperfect PHD zinc-finger domains. Filled circles indicate PHF6 mutations. (B) PHF6 mutations previously reported in T-ALL, AML and BFLS. Filled circles represent mutations in T-ALL. Triangles represent mutations in AML. Open circles represent mutations in BFLS. 1, G10fs. 2, C28fs. 3, A41fs. 4, H43fs. 5, H44fs. 6, T98fs. 7, Y105fs. 8, R116X. 9, G122X. 10, H135fs. 11, S158fs. 12, F172fs. 13, S191fs. 14, C215F and C215Y. 15, R225X. 16, K235X. 17, R257X. 18, G263fs. 19, R274X. 20, C280Y. 21, C283R. 22, T300A. 23, Y303fs and Y303X. 24, A311P. 25, S320X. 26, H329R. 27, D333fs. (C) Representative DNA sequencing chromatograms of T-ALL genomic DNA samples showing mutations in exons 6, 8, 9 and 10 of PHF6.

Figure 2.

Figure 2.

Whole-genome array CGH. Image shows array CGH (244K) analysis in one female T-ALL patient which revealed a 1.4 Mb deletion at Xq26 including the PHF6 gene (black arrow).

Similar articles

Cited by

References

    1. Uckun FM, Gaynon PS, Sensel MG, Nachman J, Trigg ME, Steinherz PG, et al. 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. - PubMed
    1. Kox C, Zimmermann M, Stanulla M, Leible S, Schrappe M, Ludwig WD, et al. 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 - PubMed
    1. Breit S, Stanulla M, Flohr T, Schrappe M, Ludwig WD, Tolle G, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood. 2006;108(4):1151–7. - PubMed
    1. Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G, et al. 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. - PubMed
    1. Zuurbier L, Homminga I, Calvert V, te Winkel ML, Buijs-Gladdines JG, Kooi C, et al. 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. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources