PHF6 mutations in myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myeloid leukemia

Bataller, Àlex; Chien, Kelly S.; Sasaki, Koji; Montalban‐Bravo, Guillermo; Kanagal‐Shamanna, Rashmi; Urrutia, Samuel; Almanza-Huante, Emmanuel; Gener-Ricos, Georgina; Ravandi, Farhad; Jabbour, Elias; Kadia, Tapan M.; Borthakur, Gautam

doi:10.1016/j.leukres.2023.107044

Cited by 3 publications

(2 citation statements)

References 19 publications

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Section: Introductionmentioning

confidence: 99%

“…Somatic PHF6 mutations were first documented in T-cell acute lymphocytic leukemia (T-ALL), where it was found to be mutated in 38% of patients (10). Subsequently, PHF6 mutations were documented in myeloid malignancies, including 3-6% of AML, myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML), as well as in 23% of mixed-phenotype acute leukemia (MPAL) (1,(11)(12)(13)(14)(15)(16). PHF6 mutations co-occur in MDS/AML with mutations in RUNX1, ASXL1, and U2AF1 (1,12,16), and a majority of PHF6 mutations are frameshift and nonsense mutations distributed throughout the gene body (16), presumably leading to null alleles and indicating that PHF6 acts as a leukemia suppressor.…”

Section: Introductionmentioning

confidence: 99%

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PHF6 suppresses self-renewal of leukemic stem cells in AML

Jalnapurkar,

Pawar,

George

et al. 2024

Preprint

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Acute myeloid leukemia is characterized by the uncontrolled proliferation of self-renewing myeloid progenitors. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its loss increases mouse HSC self-renewal without malignant transformation. We report here that Phf6 knockout increases the aggressiveness of Hoxa9-driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the in vivo hierarchy of Hoxa9-driven AML and identify a population that we term the LIC-e (leukemia initiating cells enriched) population. We find that Phf6 loss has context-specific transcriptional effects, skewing the LIC-e transcriptome to a more stem-like state. We demonstrate that LIC-e accumulation in Phf6 knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Overall, our work indicates that Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PHF6 suppresses self-renewal of leukemic stem cells in AML

Jalnapurkar,

Pawar,

George

et al. 2024

Preprint

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PHF6 mutations in chronic myelomonocytic leukemia identify a unique subset of patients with distinct phenotype and superior prognosis

Tefferi,

Fathima,

Alsugair

et al. 2024

American J Hematol

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The current study was inspired by observations from exploratory analyses of an institutional cohort with chronic myelomonocytic leukemia (CMML; N = 398) that revealed no instances of blast transformation in the seven patients with plant homeodomain finger protein 6 (PHF6) mutation (PHF6MUT). A subsequent Mayo Clinic enterprise‐wide database search identified 28 more cases with PHF6MUT. Compared with their wild‐type PHF6 counterparts (PHF6WT; N = 391), PHF6MUT cases (N = 35) were more likely to co‐express TET2 (89% vs. 45%; p < .01), RUNX1 (29% vs. 14%; p = .03), CBL (14% vs. 2%; p < .01), and U2AF1 (17% vs. 6%; p = .04) and less likely SRSF2 (23% vs. 45%; p < .01) mutation. They were also more likely to display loss of Y chromosome (LoY; 21% vs. 2%; p < .01) and platelets <100 × 109/L (83% vs. 51%; p < .01). Multivariable analysis identified PHF6MUT (HR 0.28, 95% CI 0.15–0.50) and DNMT3AMUT (HR 5.8, 95% CI 3.3–10.5) as the strongest molecular predictors of overall survival. The same was true for blast transformation‐free survival with corresponding HR (95% CI) of 0.08 (0.01–0.6) and 9.5 (3.8–23.5). At median 20 months follow‐up, blast transformation was documented in none of the 33 patients with PHF6MUT/DNMT3AWT but in 6 (32%) of 19 with DNMT3AMUT and 74 (20%) of 374 with PHF6WT/DNMT3AWT (p < .01). 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.

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PHF6 suppresses self-renewal of leukemic stem cells in AML

Jalnapurkar,

Pawar,

George

et al. 2024

Leukemia

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Acute myeloid leukemia is characterized by uncontrolled proliferation of self-renewing myeloid progenitors accompanied by a differentiation arrest. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its isolated loss increases mouse HSC self-renewal without malignant transformation. We report here that Phf6 knockout increases the aggressiveness of Hoxa9-driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the in vivo hierarchy of Hoxa9-driven AML and identify a population that we term the “LIC-e” (leukemia initiating cells enriched) population. We find that Phf6 loss expands the LIC-e population and skews its transcriptome to a more stem-like state; concordant transcriptome shifts are also observed on PHF6 knockout in a human AML cell line and in PHF6 mutant patient samples from the BEAT AML dataset. We demonstrate that LIC-e accumulation in Phf6 knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Our work indicates that Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells.

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PHF6 mutations in myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myeloid leukemia

Cited by 3 publications

References 19 publications

PHF6 suppresses self-renewal of leukemic stem cells in AML

PHF6 suppresses self-renewal of leukemic stem cells in AML

PHF6 mutations in chronic myelomonocytic leukemia identify a unique subset of patients with distinct phenotype and superior prognosis

PHF6 suppresses self-renewal of leukemic stem cells in AML

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