Somatic mutations of<i>PHF6</i>in patients with chronic myeloid leukemia in blast crisis

Li, Xianmin; Yao, Hong; Chen, Zixing; Wang, Qinrong; Zhao, Yun; Chen, Suning

doi:10.3109/10428194.2012.725203

Cited by 10 publications

(6 citation statements)

References 9 publications

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“…PHF6 mutations are rarely identified in myeloproliferative neoplasms (MPN) (0.7%), occurring in only 1.6% of chronic myelogenous leukemia ( 24 ). A screen of 81patients with CML in myeloid blast crisis identified 2 male patients with PHF6 mutations, with at least one patient showing no PHF6 mutations in the preceding chronic phase ( 65 ). This finding raises the possibility that, similar to MDS, the accumulation of PHF6 mutations might mediate progression of the disease.…”

Section: Phf6 and Hematologic Diseasementioning

confidence: 99%

PHF6 Mutations in Hematologic Malignancies

Kurzer

Weinberg

2021

Front. Oncol.

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Next generation sequencing has uncovered several genes with associated mutations in hematologic malignancies that can serve as potential biomarkers of disease. Keeping abreast of these genes is therefore of paramount importance in the field of hematology. This review focuses on PHF6, a highly conserved epigenetic transcriptional regulator that is important for neurodevelopment and hematopoiesis. PHF6 serves as a tumor suppressor protein, with PHF6 mutations and deletions often implicated in the development of T-lymphoblastic leukemia and less frequently in acute myeloid leukemia and other myeloid neoplasms. PHF6 inactivation appears to be an early event in T-lymphoblastic leukemogenesis, requiring cooperating events, including NOTCH1 mutations or overexpression of TLX1 and TLX3 for full disease development. In contrast, PHF6 mutations tend to occur later in myeloid malignancies, are frequently accompanied by RUNX1 mutations, and are often associated with disease progression. Moreover, PHF6 appears to play a role in lineage plasticity within hematopoietic malignancies, with PHF6 mutations commonly present in mixed phenotype acute leukemias with a predilection for T-lineage marker expression. Due to conflicting data, the prognostic significance of PHF6 mutations remains unclear, with a subset of studies showing no significant difference in outcomes compared to malignancies with wild-type PHF6, and other studies showing inferior outcomes in certain patients with mutated PHF6. Future studies are necessary to elucidate the role PHF6 plays in development of T-lymphoblastic leukemia, progression of myeloid malignancies, and its overall prognostic significance in hematopoietic neoplasms.

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Section: Phf6 and Hematologic Diseasementioning

confidence: 99%

PHF6 Mutations in Hematologic Malignancies

Kurzer

Weinberg

2021

Front. Oncol.

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“…Isolated cases of loss-of-function PHF6 mutations in chronic myeloid leukemia (CML) and hepatocellular carcinoma patient tumours have also been reported [ 49 , 57 ]. Interestingly, shRNA-mediated knockdown of Phf6 in a murine B-cell acute lymphoblastic leukemia (B-ALL) model was observed to significantly reduce the rates of tumour proliferation, in contrast to both T-ALL and AML models, where the loss of Phf6 correlates with enhanced tumour progression [ 24 , 58 ].…”

Section: Consequences Of Somatic Mutations Of Phf6mentioning

confidence: 99%

PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein

Todd

Ivanochko

Picketts

2015

Genes

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The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Börjeson–Forssman–Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis.

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“…1 PHF6 mutations also occur in myeloid neoplasms, including in 3% of acute myeloid leukemia 2 and 2.5% of chronic myeloid leukemia. 3 Recently, PHF6 mutations were reported in 16% to 55% of mixed phenotype acute leukemia, [4][5][6] 3% of high-grade B-cell lymphoma, 7 and in pediatric B-progenitor acute lymphoblastic leukemia, 8 suggesting that PHF6 may exert a tumor-suppressive role in multiple hematopoietic lineages. However, there is no direct functional evidence demonstrating whether these mutations contribute to pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia

McRae

Garnham

et al. 2019

Blood

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Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and β receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukemia. Our data suggest that PHF6 is a hematopoietic tumor suppressor and is important for fine-tuning hematopoietic stem and progenitor cell homeostasis.

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Somatic mutations ofPHF6in patients with chronic myeloid leukemia in blast crisis

Cited by 10 publications

References 9 publications

PHF6 Mutations in Hematologic Malignancies

PHF6 Mutations in Hematologic Malignancies

PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein

PHF6 regulates hematopoietic stem and progenitor cells and its loss synergizes with expression of TLX3 to cause leukemia

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