PHF6 mutations in adult acute myeloid leukemia

Vlierberghe, Pieter Van; Patel, Jay P.; Abdel-Wahab, Omar; Lobry, Camille; Hedvat, Cyrus V.; Balbı́n, Milagros; Nicolás, Concepción; Payer, Ángel Ramírez; Fernandez, Hugo F.; Tallman, Martin S.; Paietta, Elisabeth; Melnick, Ari; Vandenberghe, Peter; Speleman, Frank; Aifantis, Iannis; Cools, Jan; Levine, Ross L.; Ferrando, Adolfo A.

doi:10.1038/leu.2010.247

Cited by 148 publications

(119 citation statements)

References 31 publications

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“…17 Though X-linked and recessive, BFLS may also occur in women. Remarkably, a 13-fold male excess of PHF6 mutated cases in T-ALL and a 7-fold male excess in acute myeloid leukemia have been reported recently, 18,19 implying skewed inactivation of PHF6 mutations, X-homologs in females, or some other unknown mechanism for maintaining PHF6 expression. However, unlike Van Vlierberghe, 18 we observed no male excess of PHF6 mutations in T-ALL patients, and although we were able to confirm the reported excess of adult (18.6%) over pediatric (5.4%) cases of PHF6 mutations in T-ALL, both our estimates were significantly lower than the corresponding estimates of 38.1% and 15.7% in previous reports.…”

Section: Discussionmentioning

confidence: 99%

“…PHF6 mutations were detected in 38% (16/42) of adult and 16% (14/89) of pediatric T-ALL patients and rarely also in adults with acute myeloid leukemia. 18,19 PHF6 is X-linked, and tumorigenic mutations have been almost exclusively detected in male patients with either T-ALL or acute myeloid leukemia. This gender-bias has been proposed as contributing to the 3-fold higher incidence of T-ALL in males over females.…”

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confidence: 99%

“…[17][18][19] Briefly, total RNA was extracted from bone marrow mononuclear cells of 48 T-ALL cases prepared with Ficoll gradient centrifugation. RNA concentrations were measured by fluorometry.…”

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confidence: 99%

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

Wang¹,

Qiu²,

Jiang³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMutations 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 MethodsWe 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. ResultsPHF6 mutations were identified in 11/59 (18.6%) adult and 2/37 (5.4%) pediatric cases of Tcell 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. ConclusionsOverall, 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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Wang¹,

Qiu²,

Jiang³

et al. 2011

Haematologica

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“…Inactivating mutations in PHF6 are the cause of B€ orjeson-Forssman-Lehman syndrome (BFLS), an Xlinked intellectual disability (XLID) disorder (Lower et al 2002). Recently, inactivating PHF6 mutations have been identified in ;25%-30% of human T-cell ALLs (Van Vlierberghe et al 2010;Zhang et al 2012) and in 2%-3% of acute myeloid leukemias (AMLs) (Supplemental Table 5; Van Vlierberghe et al 2011;Patel et al 2012;Yoo et al 2012). While the mutational status of PHF6 has been examined in >100 human B-lineage ALLs (Van Vlierberghe et al 2010;Zhang et al 2012), no PHF6 mutations have been observed in these tumors (Supplemental Table 5), suggesting that inactivating mutations do not promote malignant growth in B-ALL.…”

Section: Resultsmentioning

confidence: 99%

A genome-scale in vivo loss-of-function screen identifies Phf6 as a lineage-specific regulator of leukemia cell growth

et al. 2015

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We performed a genome-scale shRNA screen for modulators of B-cell leukemia progression in vivo. Results from this work revealed dramatic distinctions between the relative effects of shRNAs on the growth of tumor cells in culture versus in their native microenvironment. Specifically, we identified many “context-specific” regulators of leukemia development. These included the gene encoding the zinc finger protein Phf6. While inactivating mutations in PHF6 are commonly observed in human myeloid and T-cell malignancies, we found that Phf6 suppression in B-cell malignancies impairs tumor progression. Thus, Phf6 is a “lineage-specific” cancer gene that plays opposing roles in developmentally distinct hematopoietic malignancies.

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“…The PHF6 alterations result in loss of PHF6 expression and are associated with TLX1/3-and TAL1-rearranged ALL. 17,18 The role of PHF6 in leukemogenesis is poorly understood, but the loss-offunction alterations suggest that PHF6 is a tumor suppressor.…”

Section: T-lineage Allmentioning

confidence: 99%

Genome sequencing of lymphoid malignancies

Mullighan

2013

Blood

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Our understanding of the pathogenesis of lymphoid malignancies has been transformed by next-generation sequencing. The studies in this review have used whole-genome, exome, and transcriptome sequencing to identify recurring structural genetic alterations and sequence mutations that target key cellular pathways in acute lymphoblastic leukemia (ALL) and the lymphomas. Although each tumor type is characterized by a unique genomic landscape, several cellular pathways are mutated in multiple tumor types—transcriptional regulation of differentiation, antigen receptor signaling, tyrosine kinase and Ras signaling, and epigenetic modifications—and individual genes are mutated in multiple tumors, notably TCF3, NOTCH1, MYD88, and BRAF. In addition to providing fundamental insights into tumorigenesis, these studies have also identified potential new markers for diagnosis, risk stratification, and therapeutic intervention. Several genetic alterations are intuitively “druggable” with existing agents, for example, kinase-activating lesions in high-risk B-cell ALL, NOTCH1 in both leukemia and lymphoma, and BRAF in hairy cell leukemia. Future sequencing efforts are required to comprehensively define the genetic basis of all lymphoid malignancies, examine the relative roles of germline and somatic variation, dissect the genetic basis of clonal heterogeneity, and chart a course for clinical sequencing and translation to improved therapeutic outcomes.

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PHF6 mutations in adult acute myeloid leukemia

Cited by 148 publications

References 31 publications

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

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

A genome-scale in vivo loss-of-function screen identifies Phf6 as a lineage-specific regulator of leukemia cell growth

Genome sequencing of lymphoid malignancies

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