PHF6 mutation

We show that PHIP loss phenocopies PHF6 loss, and that PHF6 requires PHIP to occupy chromatin and exert downstream transcriptional effects. Our work unifies PHF6 and PHIP, two disparate leukemia-mutated proteins, into a common functional complex that suppresses AML stemness.

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According to early findings, NGS panels are extremely effective instruments that provide an entirely new viewpoint on the disease for particular individuals. Future prognostications will depend more on NGS because those who exhibit normal cytogenetics may additionally have gene mutations.

The specific molecular signatures sustained their significant predictive performance in the context of the CMML-specific molecular prognostic model (CPSS-mol). PHF6MUT identifies a unique subset of patients with CMML characterized by thrombocytopenia, higher prevalence of LoY, and superior prognosis.

In addition, allo-HSCT could enhance the molecular response rate. Maintenance therapy post-HSCT with TKI could improve prognosis.

Finally, we demonstrate a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival are additive as PHF6MT cases with RUNX1 mutations have worse outcomes when compared to cases carrying single mutation or wild-type.

Clinical and prognostic correlations were observed according to genomic mutation profiles detected by NGS in Korean patients with AML. An NGS study with a larger cohort of patients would be beneficial to establish the significant prognostic impact on patients with AML.

This model identifies 3 subgroups at CR1: a large favorable Risk (CR1-FAV) group (231/332, 70%) with CIR at 5 years estimated at 19% (95%CI:14%-24%) (Figure B), a subgroup of Adverse risk (CR1-ADV) patients (30/332, 9%) with a 5-year CIR of 68% (95%CI:46%-82%) and an Intermediate risk (CR1-INT) group (71/332, 21%) with a 5-year CIR of 37% (95%CI:26%-48%). Conclusion T-ALL NGS-based stratification combined with WBC and MRD evaluation sharpens the prognostic classification in T-ALL and identifies a new subgroup of adverse risk patients who should benefit from innovative therapeutic approaches.

Introduction: Chronic myelomonocytic leukemia (CMML) is characterized by accumulation of classical CD14+CD16- inflammatory monocytes driven in part by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine. CMML is a disorder of profound innate immune activation, driven by GM-CSF and other pro-inflammatory cytokines. Early treatment with LENZ/AZA, a precision immunotherapeutic approach, leads to a) efficacy in INNATE-1 that exceeds historical CR rates for hypomethylating agents1,2; and b) evolving efficacy in INNATE-2, in which pro-inflammatory activity is more robust. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study.

Moreover, we reveal the ability of the LIC to differentiate and de-differentiate after leukemia initiation. Taken together our results demonstrate a transient period of plasticity during leukemia initiation where phenotypic switches appear unidirectional.

Although T-ALL and T-LBL both originate from precursor T-cells and are considered different manifestations of the same disease and the outcome of T-LBL is favorable when using T-ALL-based chemotherapy, there are differences in the gene distribution between T-LBL and T-ALL. It seems that the PI3K-Akt signaling pathway and the USP34 gene play important roles in T-LBL, but medicines targeting the USP34 gene or the PI3K-Akt pathway may be invalid.

 The distribution of gene mutations and the co-occurrence and repulsion of mutant genes in patients with ALL were closely related to the immunophenotype of the patients. The number of mutations ≥5 and the RELN mutation were significantly associated with poor prognosis in adolescent and adult patients with ALL.

RNA-sequencing analysis confirmed that Phf6 mutation altered the expression of key genes involved in HSC self-renewal and T cell activation. Our study demonstrated that Phf6 plays a critical role in fine-tuning T cells and HSC homeostasis.

Comparison of the mutational landscape at diagnosis and relapse revealed an enrichment of mutations in tumor suppressor genes (16.2% vs. 44.4%) and transcription factors (35.1 vs. 55.6%) at relapse. Our findings shed further light on the heterogeneity of pediatric AML and identified previously unappreciated alterations that may lead to improved molecular characterization and risk stratification of pediatric AML.

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Thus, PHF6 could be a potential biomarker in predicting the prognosis of UCEC patients. Depletion of PHF6 may be a novel therapeutic strategy for UCEC patients.

This study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.

Our study suggests that TP53 AML-MRC defines a very-high-risk subentity of AML in which novel therapies should be explored.

This is also in line with higher frequency of PHF6MT in sAML. Some PHF6MT cases have higher expression of lymphoid genes, which may be candidate for molecular targeted therapy.

In newly diagnosed CML patients in chronic phase, mutations in addition to BCR::ABL1 were frequently identified at diagnosis and were found to vary in their dynamics during treatment. ASXL1 mutations were most common and affected patients showed MMR less frequently at month 12, 18, and 24 compared to all other patients. ASXL1 may, after further validation, serve as an additional prognostic factor for molecular response in newly diagnosed CML patients.

2015) In conclusion, we show that Phf6 is a novel regulator of Treg cells perhaps through ADAP and glycolysis pathways. We will further explore the functions and mechanisms of the Phf6 on T cell regulation.

We proposed a refined ELN-2022 risk stratification, which re-categorized AML with t(7; 11)(p15; p15)/NUP98–HOXA9 or co-mutated DNMT3A and FLT3-ITD as adverse risk and AML with t(6; 9)(p23; q34.1)/DEK-NUP214 as intermediate risk. Refined ELN-2022 system not only worked well for OS, but also better stratified intermediate and adverse groups in terms of RFS.

Our data revealed that PHF6 mutation was associated with a lower chemotherapy response and shorter survival, suggesting that PHF6 mutation is a predictor of poor prognosis in AML.

In accordance with the treatment principles of AML-MRC, we chose an AML-like regimen for four cycles, but the patient did not achieve remission. Finally, we adhered to the treatment principles of mixed phenotype acute leukemia, and he achieved remission after a course of ALL-like regimen chemotherapy.

PHF6 maintains a chromatin structure that is permissive to B-cell identity genes, but not T-cell-specific genes (left). Loss of PHF6 leads to aberrant expression of B-cell- and T-cell-specific genes resulting from lineage promiscuity and binding of T-cell transcription factors (right).

The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine, the drug that is most commonly used to treat AML. Collectively, we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia.

While suggestive of segmental neurofibromatosis, genetic analysis revealed activating KRAS mutation and inactivating mutation in PHF6 with no evidence of NF1 mutation in germline or tumor tissue. Neither KRAS nor PHF6 have been previously reported in association with neurofibroma.

Upon statistical analysis, TTN and NOTCH1 mutations were found to be associated with prednisone resistance...Our study is the first to demonstrate the association between TTN mutation and glucocorticoid resistance in ALL. Our findings could guide strategies for overcoming drug resistance and aid in the development of drug targets.

Of utmost interest is that co-existence of PHF6 and NOTCH1 mutation status might provide an alternative for early therapeutic stratification in T-LBL. Together, our findings will not only provide new insights into the molecular and genetic mechanisms of T-LBL, but also have tangible implications for clinical practice.

We identified that IKZF1 transcripts with intron retention were upregulated in the CRLF2-high subgroup. Here, we delineated the gene expression profile of CRLF2-high T-ALL samples and unravelled the crucial role of PRC2 in CRLF2 regulation in ETP-ALL.

PDCD6, GNG5, PHF6, MAL2, SLC25A15 and PTDSS1 could be the advanced independent indicators for prognosis of BLCA patients, and TP53-mutation might be a biomarker for drug option in BLCA patients.

Single-cell RNA sequencing revealed distinct patterns of transcriptome of the hematopoietic stem/progenitor cells from the combined mutated mice, including aberrant expression of metabolic enzymes, increased expression of several oncogenes, and impairment of DNA repairs, as confirmed by the enhanced γH2AX expression in the marrow and spleen cells. We conclude that Idh2 and Phf6 mutations are synergistic in leukemogenesis, at least through overproduction of 2-hydroxyglutarate and impairment of DNA repairs.

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