Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia

Margherita Ghisi; Lev Kats; Frederick Masson; Jason Li; Tobias Kratina; Eva Vidacs; Omer Gilan; Maria A. Doyle; Andrea Newbold; Jessica E. Bolden; Kirsten A. Fairfax; Carolyn A. de Graaf; Matthew Firth; Johannes Zuber; Ross A. Dickins; Lynn M. Corcoran; Mark A. Dawson; Gabrielle T. Belz; Ricky W. Johnstone

doi:10.1016/j.ccell.2016.05.019

Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia

Margherita Ghisi
, Lev Kats
, Frederick Masson
, Jason Li
, Tobias Kratina
, Eva Vidacs
, Omer Gilan
, Maria A. Doyle
, Andrea Newbold
, Jessica E. Bolden
, Kirsten A. Fairfax
, Carolyn A. de Graaf
, Matthew Firth
, Johannes Zuber
, Ross A. Dickins
, Lynn M. Corcoran
, Mark A. Dawson
, Gabrielle T. Belz
, Ricky W. Johnstone

Australian Centre for Blood Diseases

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

30 Citations (Scopus)

Abstract

E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8;21) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8;21) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.

Original language	English
Pages (from-to)	59-74
Number of pages	16
Journal	Cancer Cell
Volume	30
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2016.05.019
Publication status	Published - 11 Jul 2016

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10.1016/j.ccell.2016.05.019

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Ghisi, M., Kats, L., Masson, F., Li, J., Kratina, T., Vidacs, E., Gilan, O., Doyle, M. A., Newbold, A., Bolden, J. E., Fairfax, K. A., de Graaf, C. A., Firth, M., Zuber, J., Dickins, R. A., Corcoran, L. M., Dawson, M. A., Belz, G. T., & Johnstone, R. W. (2016). Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia. Cancer Cell, 30(1), 59-74. https://doi.org/10.1016/j.ccell.2016.05.019

@article{80a64b24c96141d282fae973f76562ed,

title = "Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia",

abstract = "E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8;21) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8;21) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.",

author = "Margherita Ghisi and Lev Kats and Frederick Masson and Jason Li and Tobias Kratina and Eva Vidacs and Omer Gilan and Doyle, \{Maria A.\} and Andrea Newbold and Bolden, \{Jessica E.\} and Fairfax, \{Kirsten A.\} and \{de Graaf\}, \{Carolyn A.\} and Matthew Firth and Johannes Zuber and Dickins, \{Ross A.\} and Corcoran, \{Lynn M.\} and Dawson, \{Mark A.\} and Belz, \{Gabrielle T.\} and Johnstone, \{Ricky W.\}",

year = "2016",

month = jul,

day = "11",

doi = "10.1016/j.ccell.2016.05.019",

language = "English",

volume = "30",

pages = "59--74",

journal = "Cancer Cell",

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publisher = "Cell Press",

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Ghisi, M, Kats, L, Masson, F, Li, J, Kratina, T, Vidacs, E, Gilan, O, Doyle, MA, Newbold, A, Bolden, JE, Fairfax, KA, de Graaf, CA, Firth, M, Zuber, J, Dickins, RA, Corcoran, LM, Dawson, MA, Belz, GT & Johnstone, RW 2016, 'Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia', Cancer Cell, vol. 30, no. 1, pp. 59-74. https://doi.org/10.1016/j.ccell.2016.05.019

TY - JOUR

T1 - Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia

AU - Ghisi, Margherita

AU - Kats, Lev

AU - Masson, Frederick

AU - Li, Jason

AU - Kratina, Tobias

AU - Vidacs, Eva

AU - Gilan, Omer

AU - Doyle, Maria A.

AU - Newbold, Andrea

AU - Bolden, Jessica E.

AU - Fairfax, Kirsten A.

AU - de Graaf, Carolyn A.

AU - Firth, Matthew

AU - Zuber, Johannes

AU - Dickins, Ross A.

AU - Corcoran, Lynn M.

AU - Dawson, Mark A.

AU - Belz, Gabrielle T.

AU - Johnstone, Ricky W.

PY - 2016/7/11

Y1 - 2016/7/11

N2 - E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8;21) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8;21) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.

AB - E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8;21) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8;21) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.

UR - https://www.scopus.com/pages/publications/84978472913

U2 - 10.1016/j.ccell.2016.05.019

DO - 10.1016/j.ccell.2016.05.019

M3 - Article

AN - SCOPUS:84978472913

SN - 1535-6108

VL - 30

SP - 59

EP - 74

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia

Abstract

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