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

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

doi:10.15252/embj.201797994

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

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

Imperial College London

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

211 Downloads (Pure)

Abstract

While β-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 β-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, β-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 β-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 β-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 β-catenin/Hoxa9/Prmt1 in governing leukemic self-renewal.

Original language	English
Pages (from-to)	3139-3155
Journal	The EMBO journal
Volume	36
Issue number	21
Early online date	4 Oct 2017
DOIs	https://doi.org/10.15252/embj.201797994
Publication status	Published - 2 Nov 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.15252/embj.201797994

Transcriptional memory of cells_SIRIBOONPIPUTTANA_Accepred25August2017Publishedonline4October2017_GREEN AAMAccepted author manuscript, 1.97 MB

Cite this

Siriboonpiputtana, T., Zeisig, B. B., Zarowiecki, M., Fung, T. K., Mallardo, M., Tsai, C.-T., Lau, P. N. I., Hoang, Q. C., Veiga, P., Barnes, J., Lynn, C., Wilson, A., Lenhard, B., & So, C. W. E. (2017). Transcriptional memory of cells of origin overrides β-catenin requirement of MLL cancer stem cells. The EMBO journal, 36(21), 3139-3155. https://doi.org/10.15252/embj.201797994

@article{8cfc98754b184fc495edf248c23b725c,

title = "Transcriptional memory of cells of origin overrides β-catenin requirement of MLL cancer stem cells",

abstract = "While β-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 β-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, β-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 β-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 β-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 β-catenin/Hoxa9/Prmt1 in governing leukemic self-renewal.",

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

note = "{\textcopyright} 2017 The Authors.",

year = "2017",

month = nov,

day = "2",

doi = "10.15252/embj.201797994",

language = "English",

volume = "36",

pages = "3139--3155",

journal = "The EMBO journal",

issn = "0261-4189",

publisher = "Wiley-Blackwell",

number = "21",

}

TY - JOUR

T1 - Transcriptional memory of cells of origin overrides β-catenin requirement of MLL cancer stem cells

AU - Siriboonpiputtana, Teerapong

AU - Zeisig, Bernd B

AU - Zarowiecki, Magdalena

AU - Fung, Tsz Kan

AU - Mallardo, Maria

AU - Tsai, Chiou-Tsun

AU - Lau, Priscilla Nga Ieng

AU - Hoang, Quoc Chinh

AU - Veiga, Pedro

AU - Barnes, Jo

AU - Lynn, Claire

AU - Wilson, Amanda

AU - Lenhard, Boris

AU - So, Chi Wai Eric

PY - 2017/11/2

Y1 - 2017/11/2

N2 - While β-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 β-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, β-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 β-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 β-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 β-catenin/Hoxa9/Prmt1 in governing leukemic self-renewal.

AB - While β-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 β-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, β-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 β-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 β-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 β-catenin/Hoxa9/Prmt1 in governing leukemic self-renewal.

U2 - 10.15252/embj.201797994

DO - 10.15252/embj.201797994

M3 - Article

C2 - 28978671

SN - 0261-4189

VL - 36

SP - 3139

EP - 3155

JO - The EMBO journal

JF - The EMBO journal

IS - 21

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this