Transcriptional memory of cells of origin overrides ß-catenin requirement of MLL cancer stem cells.

Siriboonpiputtana, Teerapong; Zeisig, Bernd B; Zarowiecki, Magdalena; Fung, Tsz Kan; Mallardo, Maria; Tsai, Chiou-Tsun; Lau, Priscilla Nga Ieng; Hoang, Quoc Chinh; Veiga, Pedro; Barnes, Jo; Lynn, Claire; Wilson, Amanda; Lenhard, Boris; So, Chi Wai Eric

Siriboonpiputtana, Teerapong; Zeisig, Bernd B; Zarowiecki, Magdalena; Fung, Tsz Kan; Mallardo, Maria; Tsai, Chiou-Tsun; Lau, Priscilla Nga Ieng; Hoang, Quoc Chinh; Veiga, Pedro; Barnes, Jo; Lynn, Claire; Wilson, Amanda; Lenhard, Boris; So, Chi Wai Eric.

Afiliación

Siriboonpiputtana T; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Zeisig BB; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Zarowiecki M; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Fung TK; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Mallardo M; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Tsai CT; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Lau PNI; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Hoang QC; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Veiga P; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Barnes J; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Lynn C; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Wilson A; Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
Lenhard B; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, London, UK.
So CWE; Computational Regulatory Genomics, MRC London Institute of Medical Sciences, London, UK.

EMBO J ; 36(21): 3139-3155, 2017 11 02.

Article en En | MEDLINE | ID: mdl-28978671

RESUMEN

While ß-catenin has been demonstrated as an essential molecule and therapeutic target for various cancer stem cells (CSCs) including those driven by MLL fusions, here we show that transcriptional memory from cells of origin predicts AML patient survival and allows ß-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, ß-catenin regulates expression of downstream targets of a key transcriptional memory gene, Hoxa9 that is highly enriched in LSK-derived MLL-CSCs and helps sustain leukemic self-renewal. Suppression of Hoxa9 sensitizes LSK-derived MLL-CSCs to ß-catenin inhibition resulting in abolishment of CSC transcriptional program and transformation ability. In addition, further molecular and functional analyses identified Prmt1 as a key common downstream mediator for ß-catenin/Hoxa9 functions in LSK-derived MLL-CSCs. Together, these findings not only uncover an unexpectedly important role of cells of origin transcriptional memory in regulating CSC self-renewal, but also reveal a novel molecular network mediated by ß-catenin/Hoxa9/Prmt1 in governing leukemic self-renewal.

Asunto(s)

Regulación Leucémica de la Expresión Génica; Proteínas de Homeodominio/genética; Leucemia Mieloide Aguda/genética; Células Madre Neoplásicas/metabolismo; Transcripción Genética; beta Catenina/genética; Animales; Antígenos Ly/genética; Antígenos Ly/metabolismo; Proliferación Celular; Supervivencia Celular; Modelos Animales de Enfermedad; Perfilación de la Expresión Génica; Células Madre Hematopoyéticas/metabolismo; Células Madre Hematopoyéticas/patología; Proteínas de Homeodominio/antagonistas & inhibidores; Proteínas de Homeodominio/metabolismo; Humanos; Leucemia Mieloide Aguda/metabolismo; Leucemia Mieloide Aguda/mortalidad; Leucemia Mieloide Aguda/patología; Proteínas de la Membrana/genética; Proteínas de la Membrana/metabolismo; Ratones; Ratones Endogámicos C57BL; Ratones Noqueados; Células Madre Neoplásicas/patología; Proteína-Arginina N-Metiltransferasas/genética; Proteína-Arginina N-Metiltransferasas/metabolismo; Proteínas Proto-Oncogénicas c-kit/genética; Proteínas Proto-Oncogénicas c-kit/metabolismo; ARN Interferente Pequeño/genética; ARN Interferente Pequeño/metabolismo; Proteínas Represoras/genética; Proteínas Represoras/metabolismo; Transducción de Señal; Análisis de Supervivencia; beta Catenina/metabolismo

Palabras clave

Hoxa9; MLL leukemia; Prmt1; Wnt/ßcatenin; cells of origin

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transcripción Genética / Células Madre Neoplásicas / Leucemia Mieloide Aguda / Regulación Leucémica de la Expresión Génica / Proteínas de Homeodominio / Beta Catenina Tipo de estudio: Prognostic_studies Idioma: En Revista: EMBO J Año: 2017 Tipo del documento: Article Pais de publicación: Reino Unido

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