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

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

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
Externally published	Yes

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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{d3ce8aa8280441ff9996fbe4cb2526b7,

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.}",

note = "Publisher Copyright: {\textcopyright} 2016",

year = "2016",

month = jul,

day = "11",

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

language = "English",

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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.

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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

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