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A Domain Focused Screen Identifies MEAF6 as a Vulnerability in Acute Myeloid Leukemia = Una prueba centrada en el dominio identifica a MEAF6 como una vulnerabilidad en la leucemia mieloide aguda Janice Mireya Reynaga
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Reynaga, Janice Mireya, author.
- Language:
- English
- Subjects (All):
- Cellular biology.
- Biochemistry.
- Oncology.
- Genetics.
- Biophysics.
- 0379.
- 0487.
- 0786.
- 0992.
- 0369.
- Local Subjects:
- Cellular biology.
- Biochemistry.
- Oncology.
- Genetics.
- Biophysics.
- 0379.
- 0487.
- 0786.
- 0992.
- 0369.
- Physical Description:
- 1 electronic resource (61 pages)
- Contained In:
- Dissertations Abstracts International 86-12B
- Place of Publication:
- Ann Arbor : ProQuest Dissertations and Theses, 2025
- Language Note:
- English
- Summary:
- Histone acetylation is key to regulating the transition of hematopoietic stem cells to myeloid lineage cells by adding nuance to the histone code required for recruiting chromatin binding proteins. We aimed at identifying how the MOZ acetylation complex is recruited to oncogenic loci in acute myeloid leukemia by conducting a domain focused CRISPR tiling screen for all canonical members of the complex. The strongest drop-out was the least studied subunit MEAF6, which is present in both the MOZ and HBO1 complexes. Previous research has established that the MYST family histone acetyltransferase complexes, MOZ and HBO1, are involved in driving and maintaining leukemogenesis. Moreover, certain of the histone marks that they regulate - H3K9ac and H3K14ac - facilitate the processivity of RNA polymerase II to upregulate expression of Hox cluster genes and oncogenes that disrupt stem cell differentiation and self-renewal potential. Knock-out of MEAF6 and its coiled-coil domain in AML cells demonstrated a strong proliferative defect and induction of differentiation. To our surprise, MEAF6-KO also nearly fully eliminated H3K9 and K14 acetylation compared to the minimal loss of histone acetylation upon KO of the catalytic subunits KAT6A and KAT7 in previous studies. This leads us to conclude that the small "accessory" subunit, MEAF6, plays a vital role in the assembly of these two HAT complexes
- La acetilacion de histonas es clave para regular la transicion de celulas madre hematopoyeticas a celulas de linaje mieloide, anadiendo matices al codigo de histonas necesario para el reclutamiento de proteinas de union a la cromatina. Nuestro objetivo fue identificar como el complejo de acetilacion MOZ se recluta a loci oncogenicos en la leucemia mieloide aguda mediante la realizacion de un cribado de mosaicos CRISPR centrado en el dominio para todos los miembros canonicos del complejo. La subunidad menos estudiada, MEAF6, fue la que presento mayor abandono, presente tanto en los complejos MOZ como HBO1. Investigaciones previas han establecido que los complejos de histona acetiltransferasa de la familia MYST, MOZ y HBO1, participan en el impulso y mantenimiento de la leucemogenesis. Ademas, ciertas marcas de histonas que regulan (H3K9ac y H3K14ac) facilitan la procesividad de la ARN polimerasa II para regular positivamente la expresion de genes del grupo Hox y oncogenes que alteran la diferenciacion de las celulas madre y su potencial de autorrenovacion. La inactivacion de MEAF6 y su dominio superenrollado en celulas de LMA demostro un fuerte defecto proliferativo e induccion de la diferenciacion. Sorprendentemente, la inactivacion de MEAF6 tambien elimino casi por completo la acetilacion de H3K9 y K14, en comparacion con la minima perdida de acetilacion de histonas tras la inactivacion de las subunidades cataliticas KAT6A y KAT7 en estudios previos. Esto nos lleva a concluir que la pequena subunidad "accesoria", MEAF6, desempena un papel vital en el ensamblaje de estos dos complejos HAT
- Notes:
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- Advisors: Blanco, M. Andres Committee members: Marmorstein, Ronen; Wan, Liling; Zaret, Kenneth S.; Bhoj, Elizabeth
- Ph.D. University of Pennsylvania 2025
- Local Notes:
- School code: 0175
- ISBN:
- 9798280759961
- Access Restriction:
- Restricted for use by site license
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