RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis

Ryan M. Carr; Denis Vorobyev; Terra Lasho; David L. Marks; Ezequiel J. Tolosa; Alexis Vedder; Luciana L. Almada; Andrey Yurcheko; Ismael Padioleau; Bonnie Alver; Giacomo Coltro; Moritz Binder; Stephanie L. Safgren; Isaac Horn; Xiaona You; Eric Solary; Maria E. Balasis; Kurt Berger; James Hiebert; Thomas Witzig; Ajinkya Buradkar; Temeida Graf; Peter Valent; Abhishek A. Mangaonkar; Keith D. Robertson; Matthew T. Howard; Scott H. Kaufmann; Christopher Pin; Martin E. Fernandez-Zapico; Klaus Geissler; Nathalie Droin; Eric Padron; Jing Zhang; Sergey Nikolaev; Mrinal M. Patnaik

doi:10.1038/s41467-021-23186-w

RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis

Ryan M. Carr, Denis Vorobyev, Terra Lasho, David L. Marks, Ezequiel J. Tolosa, Alexis Vedder, Luciana L. Almada, Andrey Yurcheko, Ismael Padioleau, Bonnie Alver, Giacomo Coltro, Moritz Binder, Stephanie L. Safgren, Isaac Horn, Xiaona You, Eric Solary, Maria E. Balasis, Kurt Berger, James Hiebert, Thomas WitzigAjinkya Buradkar, Temeida Graf, Peter Valent, Abhishek A. Mangaonkar, Keith D. Robertson, Matthew T. Howard, Scott H. Kaufmann, Christopher Pin, Martin E. Fernandez-Zapico, Klaus Geissler, Nathalie Droin, Eric Padron, Jing Zhang, Sergey Nikolaev, Mrinal M. Patnaik

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Abstract

Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS^G12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-Nras^G12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.

Original language	English
Article number	2901
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23186-w
Publication status	Published - 1 Dec 2021

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Carr, R. M., Vorobyev, D., Lasho, T., Marks, D. L., Tolosa, E. J., Vedder, A., Almada, L. L., Yurcheko, A., Padioleau, I., Alver, B., Coltro, G., Binder, M., Safgren, S. L., Horn, I., You, X., Solary, E., Balasis, M. E., Berger, K., Hiebert, J., ... Patnaik, M. M. (2021). RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis. Nature Communications, 12(1), Article 2901. https://doi.org/10.1038/s41467-021-23186-w

@article{cfc39f625bfd4a2fb076fb7a1ba9315b,

title = "RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis",

abstract = "Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.",

author = "Carr, {Ryan M.} and Denis Vorobyev and Terra Lasho and Marks, {David L.} and Tolosa, {Ezequiel J.} and Alexis Vedder and Almada, {Luciana L.} and Andrey Yurcheko and Ismael Padioleau and Bonnie Alver and Giacomo Coltro and Moritz Binder and Safgren, {Stephanie L.} and Isaac Horn and Xiaona You and Eric Solary and Balasis, {Maria E.} and Kurt Berger and James Hiebert and Thomas Witzig and Ajinkya Buradkar and Temeida Graf and Peter Valent and Mangaonkar, {Abhishek A.} and Robertson, {Keith D.} and Howard, {Matthew T.} and Kaufmann, {Scott H.} and Christopher Pin and Fernandez-Zapico, {Martin E.} and Klaus Geissler and Nathalie Droin and Eric Padron and Jing Zhang and Sergey Nikolaev and Patnaik, {Mrinal M.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-23186-w",

language = "English",

volume = "12",

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Carr, RM, Vorobyev, D, Lasho, T, Marks, DL, Tolosa, EJ, Vedder, A, Almada, LL, Yurcheko, A, Padioleau, I, Alver, B, Coltro, G, Binder, M, Safgren, SL, Horn, I, You, X, Solary, E, Balasis, ME, Berger, K, Hiebert, J, Witzig, T, Buradkar, A, Graf, T, Valent, P, Mangaonkar, AA, Robertson, KD, Howard, MT, Kaufmann, SH, Pin, C, Fernandez-Zapico, ME, Geissler, K, Droin, N, Padron, E, Zhang, J, Nikolaev, S & Patnaik, MM 2021, 'RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis', Nature Communications, vol. 12, no. 1, 2901. https://doi.org/10.1038/s41467-021-23186-w

TY - JOUR

T1 - RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis

AU - Carr, Ryan M.

AU - Vorobyev, Denis

AU - Lasho, Terra

AU - Marks, David L.

AU - Tolosa, Ezequiel J.

AU - Vedder, Alexis

AU - Almada, Luciana L.

AU - Yurcheko, Andrey

AU - Padioleau, Ismael

AU - Alver, Bonnie

AU - Coltro, Giacomo

AU - Binder, Moritz

AU - Safgren, Stephanie L.

AU - Horn, Isaac

AU - You, Xiaona

AU - Solary, Eric

AU - Balasis, Maria E.

AU - Berger, Kurt

AU - Hiebert, James

AU - Witzig, Thomas

AU - Buradkar, Ajinkya

AU - Graf, Temeida

AU - Valent, Peter

AU - Mangaonkar, Abhishek A.

AU - Robertson, Keith D.

AU - Howard, Matthew T.

AU - Kaufmann, Scott H.

AU - Pin, Christopher

AU - Fernandez-Zapico, Martin E.

AU - Geissler, Klaus

AU - Droin, Nathalie

AU - Padron, Eric

AU - Zhang, Jing

AU - Nikolaev, Sergey

AU - Patnaik, Mrinal M.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.

AB - Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.

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U2 - 10.1038/s41467-021-23186-w

DO - 10.1038/s41467-021-23186-w

M3 - Article

C2 - 34006870

AN - SCOPUS:85106160675

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2901

ER -

RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis

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