Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting

Yasuo Kubota, Xiaorong Gu, Laila Terkawi, Juraj Bodo, Bartlomiej P. Przychodzen, Hussein Awada, Nakisha Williams, Carmelo Gurnari, Naomi Kawashima, Mai Aly, Arda Durmaz, Minako Mori, Ben Ponvilawan, Tariq Kewan, Waled Bahaj, Manja Meggendorfer, Babal K. Jha, Valeria Visconte, Heesun J. Rogers, Torsten Haferlach and Jaroslaw P. Maciejewski ()
Additional contact information
Yasuo Kubota: Taussig Cancer Institute, Cleveland Clinic
Xiaorong Gu: Taussig Cancer Institute, Cleveland Clinic
Laila Terkawi: Taussig Cancer Institute, Cleveland Clinic
Juraj Bodo: Cleveland Clinic
Bartlomiej P. Przychodzen: Taussig Cancer Institute, Cleveland Clinic
Hussein Awada: Taussig Cancer Institute, Cleveland Clinic
Nakisha Williams: Taussig Cancer Institute, Cleveland Clinic
Carmelo Gurnari: Taussig Cancer Institute, Cleveland Clinic
Naomi Kawashima: Taussig Cancer Institute, Cleveland Clinic
Mai Aly: Taussig Cancer Institute, Cleveland Clinic
Arda Durmaz: Taussig Cancer Institute, Cleveland Clinic
Minako Mori: Taussig Cancer Institute, Cleveland Clinic
Ben Ponvilawan: Taussig Cancer Institute, Cleveland Clinic
Tariq Kewan: Taussig Cancer Institute, Cleveland Clinic
Waled Bahaj: Taussig Cancer Institute, Cleveland Clinic
Manja Meggendorfer: MLL Munich Leukemia Laboratory
Babal K. Jha: Taussig Cancer Institute, Cleveland Clinic
Valeria Visconte: Taussig Cancer Institute, Cleveland Clinic
Heesun J. Rogers: Cleveland Clinic
Torsten Haferlach: MLL Munich Leukemia Laboratory
Jaroslaw P. Maciejewski: Taussig Cancer Institute, Cleveland Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 are co-mutated with PHF6. In contrast, female cases reveal co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis reveals a direct interaction between PHF6 and RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. 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.

Date: 2024
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DOI: 10.1038/s41467-024-46134-w

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