Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia

Mark D. McKenzie; Margherita Ghisi; Ethan P. Oxley; Steven Ngo; L. Cimmino; Cécile Esnault; Ruijie Liu; Jessica M. Salmon; Charles C. Bell; Nouraiz Ahmed; Michael Erlichster; Matthew T. Witkowski; Grace J. Liu; Michael Chopin; Aleksandar Dakic; Emilia Simankowicz; Giovanna Pomilio; Tina Vu; P. Krsmanovic; S. Su; Luyi Tian; Tracey M. Baldwin; Daniela A. Zalcenstein; Ladina DiRago; Shu Wang; Donald Metcalf; Ricky W. Johnstone; B. A. Croker; Graeme I. Lancaster; Andrew J. Murphy; Shalin H. Naik; Stephen L. Nutt; V. Pospisil; Timm Schroeder; Meaghan Wall; Mark A. Dawson; Andrew H. Wei; Hugues de Thé; Matthew E. Ritchie; Johannes Zuber; Ross A. Dickins

doi:10.1016/j.stem.2019.07.001

Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia

Mark D. McKenzie, Margherita Ghisi, Ethan P. Oxley, Steven Ngo, L. Cimmino, Cécile Esnault, Ruijie Liu, Jessica M. Salmon, Charles C. Bell, Nouraiz Ahmed, Michael Erlichster, Matthew T. Witkowski, Grace J. Liu, Michael Chopin, Aleksandar Dakic, Emilia Simankowicz, Giovanna Pomilio, Tina Vu, P. Krsmanovic, S. SuLuyi Tian, Tracey M. Baldwin, Daniela A. Zalcenstein, Ladina DiRago, Shu Wang, Donald Metcalf, Ricky W. Johnstone, B. A. Croker, Graeme I. Lancaster, Andrew J. Murphy, Shalin H. Naik, Stephen L. Nutt, V. Pospisil, Timm Schroeder, Meaghan Wall, Mark A. Dawson, Andrew H. Wei, Hugues de Thé, Matthew E. Ritchie, Johannes Zuber, Ross A. Dickins

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

61 Citations (Scopus)

Abstract

Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states. Intratumoral phenotypic heterogeneity in acute myeloid leukemia (AML) and many other cancers is thought to follow a hierarchical cancer stem cell model. Dickins and colleagues show here that mature, non-leukemogenic AML cells can reacquire leukemia-initiating activity and promote disease progression through de-differentiation.

Original language	English
Pages (from-to)	258-272.e9
Number of pages	24
Journal	Cell Stem Cell
Volume	25
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2019.07.001
Publication status	Published - 1 Aug 2019

Keywords

acute myeloid leukemia
acute promyelocytic leukemia
cancer stem cell
differentiation therapy
leukemia stem cell
myelopoiesis
pioneer factor
PU.1
retinoic acid
transcription factor

UN SDGs

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

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10.1016/j.stem.2019.07.001

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McKenzie, M. D., Ghisi, M., Oxley, E. P., Ngo, S., Cimmino, L., Esnault, C., Liu, R., Salmon, J. M., Bell, C. C., Ahmed, N., Erlichster, M., Witkowski, M. T., Liu, G. J., Chopin, M., Dakic, A., Simankowicz, E., Pomilio, G., Vu, T., Krsmanovic, P., ... Dickins, R. A. (2019). Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia. Cell Stem Cell, 25(2), 258-272.e9. https://doi.org/10.1016/j.stem.2019.07.001

@article{b2c912c3b1784379b3d916a3da2d038b,

title = "Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia",

abstract = "Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states. Intratumoral phenotypic heterogeneity in acute myeloid leukemia (AML) and many other cancers is thought to follow a hierarchical cancer stem cell model. Dickins and colleagues show here that mature, non-leukemogenic AML cells can reacquire leukemia-initiating activity and promote disease progression through de-differentiation.",

keywords = "acute myeloid leukemia, acute promyelocytic leukemia, cancer stem cell, differentiation therapy, leukemia stem cell, myelopoiesis, pioneer factor, PU.1, retinoic acid, transcription factor",

author = "McKenzie, {Mark D.} and Margherita Ghisi and Oxley, {Ethan P.} and Steven Ngo and L. Cimmino and C{\'e}cile Esnault and Ruijie Liu and Salmon, {Jessica M.} and Bell, {Charles C.} and Nouraiz Ahmed and Michael Erlichster and Witkowski, {Matthew T.} and Liu, {Grace J.} and Michael Chopin and Aleksandar Dakic and Emilia Simankowicz and Giovanna Pomilio and Tina Vu and P. Krsmanovic and S. Su and Luyi Tian and Baldwin, {Tracey M.} and Zalcenstein, {Daniela A.} and Ladina DiRago and Shu Wang and Donald Metcalf and Johnstone, {Ricky W.} and Croker, {B. A.} and Lancaster, {Graeme I.} and Murphy, {Andrew J.} and Naik, {Shalin H.} and Nutt, {Stephen L.} and V. Pospisil and Timm Schroeder and Meaghan Wall and Dawson, {Mark A.} and Wei, {Andrew H.} and {de Th{\'e}}, Hugues and Ritchie, {Matthew E.} and Johannes Zuber and Dickins, {Ross A.}",

year = "2019",

month = aug,

day = "1",

doi = "10.1016/j.stem.2019.07.001",

language = "English",

volume = "25",

pages = "258--272.e9",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Elsevier",

number = "2",

}

McKenzie, MD, Ghisi, M, Oxley, EP, Ngo, S, Cimmino, L, Esnault, C, Liu, R, Salmon, JM, Bell, CC, Ahmed, N, Erlichster, M, Witkowski, MT, Liu, GJ, Chopin, M, Dakic, A, Simankowicz, E, Pomilio, G, Vu, T, Krsmanovic, P, Su, S, Tian, L, Baldwin, TM, Zalcenstein, DA, DiRago, L, Wang, S, Metcalf, D, Johnstone, RW, Croker, BA, Lancaster, GI , Murphy, AJ, Naik, SH, Nutt, SL, Pospisil, V, Schroeder, T, Wall, M, Dawson, MA, Wei, AH, de Thé, H, Ritchie, ME, Zuber, J & Dickins, RA 2019, 'Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia', Cell Stem Cell, vol. 25, no. 2, pp. 258-272.e9. https://doi.org/10.1016/j.stem.2019.07.001

TY - JOUR

T1 - Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia

AU - McKenzie, Mark D.

AU - Ghisi, Margherita

AU - Oxley, Ethan P.

AU - Ngo, Steven

AU - Cimmino, L.

AU - Esnault, Cécile

AU - Liu, Ruijie

AU - Salmon, Jessica M.

AU - Bell, Charles C.

AU - Ahmed, Nouraiz

AU - Erlichster, Michael

AU - Witkowski, Matthew T.

AU - Liu, Grace J.

AU - Chopin, Michael

AU - Dakic, Aleksandar

AU - Simankowicz, Emilia

AU - Pomilio, Giovanna

AU - Vu, Tina

AU - Krsmanovic, P.

AU - Su, S.

AU - Tian, Luyi

AU - Baldwin, Tracey M.

AU - Zalcenstein, Daniela A.

AU - DiRago, Ladina

AU - Wang, Shu

AU - Metcalf, Donald

AU - Johnstone, Ricky W.

AU - Croker, B. A.

AU - Lancaster, Graeme I.

AU - Murphy, Andrew J.

AU - Naik, Shalin H.

AU - Nutt, Stephen L.

AU - Pospisil, V.

AU - Schroeder, Timm

AU - Wall, Meaghan

AU - Dawson, Mark A.

AU - Wei, Andrew H.

AU - de Thé, Hugues

AU - Ritchie, Matthew E.

AU - Zuber, Johannes

AU - Dickins, Ross A.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states. Intratumoral phenotypic heterogeneity in acute myeloid leukemia (AML) and many other cancers is thought to follow a hierarchical cancer stem cell model. Dickins and colleagues show here that mature, non-leukemogenic AML cells can reacquire leukemia-initiating activity and promote disease progression through de-differentiation.

AB - Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states. Intratumoral phenotypic heterogeneity in acute myeloid leukemia (AML) and many other cancers is thought to follow a hierarchical cancer stem cell model. Dickins and colleagues show here that mature, non-leukemogenic AML cells can reacquire leukemia-initiating activity and promote disease progression through de-differentiation.

KW - acute myeloid leukemia

KW - acute promyelocytic leukemia

KW - cancer stem cell

KW - differentiation therapy

KW - leukemia stem cell

KW - myelopoiesis

KW - pioneer factor

KW - PU.1

KW - retinoic acid

KW - transcription factor

UR - http://www.scopus.com/inward/record.url?scp=85069555508&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2019.07.001

DO - 10.1016/j.stem.2019.07.001

M3 - Article

AN - SCOPUS:85069555508

SN - 1934-5909

VL - 25

SP - 258-272.e9

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -

Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Overcoming the differentiation block in acute myeloid leukaemia

Tumour suppressive mechanisms of CEBPA and PU.1 in acute myeloid leukaemia

Cite this

Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Overcoming the differentiation block in acute myeloid leukaemia

Tumour suppressive mechanisms of CEBPA and PU.1 in acute myeloid leukaemia

Cite this