Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth

Sophie G. Kellaway; Sandeep Potluri; Peter Keane; Helen J. Blair; Luke Ames; Alice Worker; Paulynn S. Chin; Anetta Ptasinska; Polina K. Derevyanko; Assunta Adamo; Daniel J. L. Coleman; Naeem Khan; Salam A. Assi; Anja Krippner-Heidenreich; Manoj Raghavan; Peter N. Cockerill; Olaf Heidenreich; Constanze Bonifer

doi:10.1038/s41467-024-45691-4

Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth

Sophie G. Kellaway^*, Sandeep Potluri, Peter Keane, Helen J. Blair, Luke Ames, Alice Worker, Paulynn S. Chin, Anetta Ptasinska, Polina K. Derevyanko, Assunta Adamo, Daniel J. L. Coleman, Naeem Khan, Salam A. Assi, Anja Krippner-Heidenreich, Manoj Raghavan, Peter N. Cockerill, Olaf Heidenreich, Constanze Bonifer^*

^*Corresponding author for this work

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

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Abstract

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.

Original language	English
Article number	1359
Number of pages	22
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-45691-4
Publication status	Published - 14 Feb 2024

Bibliographical note

Acknowledgments:
This work was funded by grants to C.B. and P.N.C. from Blood Cancer UK (20006), a grant from the Medical Research Council (MR/S021469/1) to C.B., P.N.C and O.H, a Cancer Research UK programme grant (C27943/A23389) and a KIKA programme grant (329) to OH, a Leukemia UK John Goldman Fellowship (2021/JGF/001) to D.J.L.C and a Cancer Research UK studentship to A.A. Benralizumab was obtained from Astra Zeneca in the context of the Open Innovation scheme. We would like to thank the West Midlands Regional Genetics Laboratory for supplying mutation data linked to AML patient samples. The authors would like to acknowledge Celina Whalley of Genomics Birmingham and Guillaume Desanti of the University of Birmingham Flow Cytometry facility for support of next-generation sequencing and cell sorting experiments. We would also like to thank Hesta McNeill and Samantha Jepson Gosling of Newcastle University, and Mauricio Ferrao Blanco, Alicia Perzolli, Elizabeth Schweighart, Bexultan Kazybay, Aleksandra Balwierz and Philip Lijnzaad from the Princess Maxima Center for their technical assistance. Finally, thanks to Ellen Rothenberg for an illuminating conversation regarding the KIT/KDR shared enhancer.

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10.1038/s41467-024-45691-4Licence: Creative Commons: Attribution (CC BY)

KellawayS2024LeukemicFinal published version, 3.44 MBLicence: Creative Commons: Attribution (CC BY)

Pharmaceutical targeting of RAS in Acute Myeloid Leukaemia with RAS mutations or FLT3-ITD
Coleman, D.
LEUKAEMIA UK
1/01/22 → 29/02/24
Project: Research
The role of RUNX1 and the AP-1 transcription factor family in t(8;21) AML
Cockerill, P. & Bonifer, C.
BLOODWISE
1/10/20 → 31/12/23
Project: Research
Finding therapeutic targets in FLT3-ITD AML using a systems biology approach
Cockerill, P. & Bonifer, C.
Medical Research Council
1/09/19 → 31/12/23
Project: Research Councils

Cite this

Kellaway, S. G., Potluri, S., Keane, P., Blair, H. J., Ames, L., Worker, A., Chin, P. S., Ptasinska, A., Derevyanko, P. K., Adamo, A., Coleman, D. J. L., Khan, N., Assi, S. A., Krippner-Heidenreich, A., Raghavan, M., Cockerill, P. N., Heidenreich, O., & Bonifer, C. (2024). Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth. Nature Communications, 15(1), Article 1359. https://doi.org/10.1038/s41467-024-45691-4

@article{e811af71ba9f4c458a68b2b49592b63e,

title = "Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth",

abstract = "Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.",

author = "Kellaway, {Sophie G.} and Sandeep Potluri and Peter Keane and Blair, {Helen J.} and Luke Ames and Alice Worker and Chin, {Paulynn S.} and Anetta Ptasinska and Derevyanko, {Polina K.} and Assunta Adamo and Coleman, {Daniel J. L.} and Naeem Khan and Assi, {Salam A.} and Anja Krippner-Heidenreich and Manoj Raghavan and Cockerill, {Peter N.} and Olaf Heidenreich and Constanze Bonifer",

note = "Acknowledgments: This work was funded by grants to C.B. and P.N.C. from Blood Cancer UK (20006), a grant from the Medical Research Council (MR/S021469/1) to C.B., P.N.C and O.H, a Cancer Research UK programme grant (C27943/A23389) and a KIKA programme grant (329) to OH, a Leukemia UK John Goldman Fellowship (2021/JGF/001) to D.J.L.C and a Cancer Research UK studentship to A.A. Benralizumab was obtained from Astra Zeneca in the context of the Open Innovation scheme. We would like to thank the West Midlands Regional Genetics Laboratory for supplying mutation data linked to AML patient samples. The authors would like to acknowledge Celina Whalley of Genomics Birmingham and Guillaume Desanti of the University of Birmingham Flow Cytometry facility for support of next-generation sequencing and cell sorting experiments. We would also like to thank Hesta McNeill and Samantha Jepson Gosling of Newcastle University, and Mauricio Ferrao Blanco, Alicia Perzolli, Elizabeth Schweighart, Bexultan Kazybay, Aleksandra Balwierz and Philip Lijnzaad from the Princess Maxima Center for their technical assistance. Finally, thanks to Ellen Rothenberg for an illuminating conversation regarding the KIT/KDR shared enhancer.",

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day = "14",

doi = "10.1038/s41467-024-45691-4",

language = "English",

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journal = "Nature Communications",

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Kellaway, SG, Potluri, S, Keane, P, Blair, HJ, Ames, L, Worker, A, Chin, PS, Ptasinska, A, Derevyanko, PK, Adamo, A, Coleman, DJL, Khan, N, Assi, SA, Krippner-Heidenreich, A, Raghavan, M , Cockerill, PN, Heidenreich, O & Bonifer, C 2024, 'Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth', Nature Communications, vol. 15, no. 1, 1359. https://doi.org/10.1038/s41467-024-45691-4

TY - JOUR

T1 - Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth

AU - Kellaway, Sophie G.

AU - Potluri, Sandeep

AU - Keane, Peter

AU - Blair, Helen J.

AU - Ames, Luke

AU - Worker, Alice

AU - Chin, Paulynn S.

AU - Ptasinska, Anetta

AU - Derevyanko, Polina K.

AU - Adamo, Assunta

AU - Coleman, Daniel J. L.

AU - Khan, Naeem

AU - Assi, Salam A.

AU - Krippner-Heidenreich, Anja

AU - Raghavan, Manoj

AU - Cockerill, Peter N.

AU - Heidenreich, Olaf

AU - Bonifer, Constanze

N1 - Acknowledgments: This work was funded by grants to C.B. and P.N.C. from Blood Cancer UK (20006), a grant from the Medical Research Council (MR/S021469/1) to C.B., P.N.C and O.H, a Cancer Research UK programme grant (C27943/A23389) and a KIKA programme grant (329) to OH, a Leukemia UK John Goldman Fellowship (2021/JGF/001) to D.J.L.C and a Cancer Research UK studentship to A.A. Benralizumab was obtained from Astra Zeneca in the context of the Open Innovation scheme. We would like to thank the West Midlands Regional Genetics Laboratory for supplying mutation data linked to AML patient samples. The authors would like to acknowledge Celina Whalley of Genomics Birmingham and Guillaume Desanti of the University of Birmingham Flow Cytometry facility for support of next-generation sequencing and cell sorting experiments. We would also like to thank Hesta McNeill and Samantha Jepson Gosling of Newcastle University, and Mauricio Ferrao Blanco, Alicia Perzolli, Elizabeth Schweighart, Bexultan Kazybay, Aleksandra Balwierz and Philip Lijnzaad from the Princess Maxima Center for their technical assistance. Finally, thanks to Ellen Rothenberg for an illuminating conversation regarding the KIT/KDR shared enhancer.

PY - 2024/2/14

Y1 - 2024/2/14

N2 - Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.

AB - Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.

U2 - 10.1038/s41467-024-45691-4

DO - 10.1038/s41467-024-45691-4

M3 - Article

C2 - 38355578

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1359

ER -

Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth

Abstract

Bibliographical note

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Projects

Pharmaceutical targeting of RAS in Acute Myeloid Leukaemia with RAS mutations or FLT3-ITD

The role of RUNX1 and the AP-1 transcription factor family in t(8;21) AML

Finding therapeutic targets in FLT3-ITD AML using a systems biology approach

Cite this