Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia

Yinghui Zhu, Xin He, Yi Chun Lin, Haojie Dong, Lei Zhang, Xianwei Chen, Zhihao Wang, Yudao Shen, Min Li, Hanying Wang, Jie Sun, Le Xuan Nguyen, Han Zhang, Wenjuan Jiang, Yanzhong Yang, Jianjun Chen, Markus Mu¨schen, Chun Wei Chen, Marina Y. Konopleva, Weili SunJian Jin, Nadia Carlesso, Guido Marcucci, Yun Luo, Ling Li

Research output: Contribution to journalArticle

Abstract

Relapse remains the main cause of MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL) treatment failure resulting from persistence of drug-resistant clones after conventional chemotherapy treatment or targeted therapy. Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy. PRMT1, which deposits an asymmetric dimethylarginine mark on histone/non-histone proteins, is reportedly overexpressed in various cancers. Here, we demonstrate elevated PRMT1 levels in MLL-r ALL cells and show that inhibition of PRMT1 significantly suppresses leukemic cell growth and survival.Mechanistically,we reveal that PRMT1 methylates Fms-like receptor tyrosine kinase 3 (FLT3) at arginine (R) residues 972 and 973 (R972/973), and its oncogenic function in MLL-r ALL cells is FLT3 methylation dependent. Both biochemistry and computational analysis demonstrate that R972/973 methylation could facilitate recruitment of adaptor proteins to FLT3 in a phospho-tyrosine (Y) residue 969 (Y969) dependent or independent manner. Cells expressing R972/973 methylation-deficient FLT3 exhibited more robust apoptosis and growth inhibition than did Y969 phosphorylation-deficient FLT3-transduced cells.We also show that the capacity of the type I PRMT inhibitor MS023 to inhibit leukemia cell viability parallels baseline FLT3 R972/973methylation levels. Finally, combining FLT3 tyrosine kinase inhibitor PKC412 with MS023 treatment enhanced elimination of MLL-r ALL cells relative to PKC412 treatment alone in patient-derived mouse xenografts. These results indicate that abolishing FLT3 arginine methylation through PRMT1 inhibition represents a promising strategy to target MLL-r ALL cells.

Original languageEnglish (US)
Pages (from-to)1257-1268
Number of pages12
JournalBlood
Volume134
Issue number15
DOIs
StatePublished - Oct 10 2019
Externally publishedYes

Fingerprint

fms-Like Tyrosine Kinase 3
Methylation
Receptor Protein-Tyrosine Kinases
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Maintenance
4'-N-benzoylstaurosporine
Arginine
Cell Survival
Histone Code
Cells
Therapeutics
Biochemistry
Phosphorylation
Chemotherapy
Cell growth
Growth
Treatment Failure
Heterografts
Histones
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Zhu, Y., He, X., Lin, Y. C., Dong, H., Zhang, L., Chen, X., ... Li, L. (2019). Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia. Blood, 134(15), 1257-1268. https://doi.org/10.1182/blood.2019002457

Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia. / Zhu, Yinghui; He, Xin; Lin, Yi Chun; Dong, Haojie; Zhang, Lei; Chen, Xianwei; Wang, Zhihao; Shen, Yudao; Li, Min; Wang, Hanying; Sun, Jie; Nguyen, Le Xuan; Zhang, Han; Jiang, Wenjuan; Yang, Yanzhong; Chen, Jianjun; Mu¨schen, Markus; Chen, Chun Wei; Konopleva, Marina Y.; Sun, Weili; Jin, Jian; Carlesso, Nadia; Marcucci, Guido; Luo, Yun; Li, Ling.

In: Blood, Vol. 134, No. 15, 10.10.2019, p. 1257-1268.

Research output: Contribution to journalArticle

Zhu, Y, He, X, Lin, YC, Dong, H, Zhang, L, Chen, X, Wang, Z, Shen, Y, Li, M, Wang, H, Sun, J, Nguyen, LX, Zhang, H, Jiang, W, Yang, Y, Chen, J, Mu¨schen, M, Chen, CW, Konopleva, MY, Sun, W, Jin, J, Carlesso, N, Marcucci, G, Luo, Y & Li, L 2019, 'Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia', Blood, vol. 134, no. 15, pp. 1257-1268. https://doi.org/10.1182/blood.2019002457
Zhu, Yinghui ; He, Xin ; Lin, Yi Chun ; Dong, Haojie ; Zhang, Lei ; Chen, Xianwei ; Wang, Zhihao ; Shen, Yudao ; Li, Min ; Wang, Hanying ; Sun, Jie ; Nguyen, Le Xuan ; Zhang, Han ; Jiang, Wenjuan ; Yang, Yanzhong ; Chen, Jianjun ; Mu¨schen, Markus ; Chen, Chun Wei ; Konopleva, Marina Y. ; Sun, Weili ; Jin, Jian ; Carlesso, Nadia ; Marcucci, Guido ; Luo, Yun ; Li, Ling. / Targeting PRMT1-mediated FLT3 methylation disrupts maintenance of MLL-rearranged acute lymphoblastic leukemia. In: Blood. 2019 ; Vol. 134, No. 15. pp. 1257-1268.
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abstract = "Relapse remains the main cause of MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL) treatment failure resulting from persistence of drug-resistant clones after conventional chemotherapy treatment or targeted therapy. Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy. PRMT1, which deposits an asymmetric dimethylarginine mark on histone/non-histone proteins, is reportedly overexpressed in various cancers. Here, we demonstrate elevated PRMT1 levels in MLL-r ALL cells and show that inhibition of PRMT1 significantly suppresses leukemic cell growth and survival.Mechanistically,we reveal that PRMT1 methylates Fms-like receptor tyrosine kinase 3 (FLT3) at arginine (R) residues 972 and 973 (R972/973), and its oncogenic function in MLL-r ALL cells is FLT3 methylation dependent. Both biochemistry and computational analysis demonstrate that R972/973 methylation could facilitate recruitment of adaptor proteins to FLT3 in a phospho-tyrosine (Y) residue 969 (Y969) dependent or independent manner. Cells expressing R972/973 methylation-deficient FLT3 exhibited more robust apoptosis and growth inhibition than did Y969 phosphorylation-deficient FLT3-transduced cells.We also show that the capacity of the type I PRMT inhibitor MS023 to inhibit leukemia cell viability parallels baseline FLT3 R972/973methylation levels. Finally, combining FLT3 tyrosine kinase inhibitor PKC412 with MS023 treatment enhanced elimination of MLL-r ALL cells relative to PKC412 treatment alone in patient-derived mouse xenografts. These results indicate that abolishing FLT3 arginine methylation through PRMT1 inhibition represents a promising strategy to target MLL-r ALL cells.",
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AU - Zhu, Yinghui

AU - He, Xin

AU - Lin, Yi Chun

AU - Dong, Haojie

AU - Zhang, Lei

AU - Chen, Xianwei

AU - Wang, Zhihao

AU - Shen, Yudao

AU - Li, Min

AU - Wang, Hanying

AU - Sun, Jie

AU - Nguyen, Le Xuan

AU - Zhang, Han

AU - Jiang, Wenjuan

AU - Yang, Yanzhong

AU - Chen, Jianjun

AU - Mu¨schen, Markus

AU - Chen, Chun Wei

AU - Konopleva, Marina Y.

AU - Sun, Weili

AU - Jin, Jian

AU - Carlesso, Nadia

AU - Marcucci, Guido

AU - Luo, Yun

AU - Li, Ling

PY - 2019/10/10

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N2 - Relapse remains the main cause of MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL) treatment failure resulting from persistence of drug-resistant clones after conventional chemotherapy treatment or targeted therapy. Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy. PRMT1, which deposits an asymmetric dimethylarginine mark on histone/non-histone proteins, is reportedly overexpressed in various cancers. Here, we demonstrate elevated PRMT1 levels in MLL-r ALL cells and show that inhibition of PRMT1 significantly suppresses leukemic cell growth and survival.Mechanistically,we reveal that PRMT1 methylates Fms-like receptor tyrosine kinase 3 (FLT3) at arginine (R) residues 972 and 973 (R972/973), and its oncogenic function in MLL-r ALL cells is FLT3 methylation dependent. Both biochemistry and computational analysis demonstrate that R972/973 methylation could facilitate recruitment of adaptor proteins to FLT3 in a phospho-tyrosine (Y) residue 969 (Y969) dependent or independent manner. Cells expressing R972/973 methylation-deficient FLT3 exhibited more robust apoptosis and growth inhibition than did Y969 phosphorylation-deficient FLT3-transduced cells.We also show that the capacity of the type I PRMT inhibitor MS023 to inhibit leukemia cell viability parallels baseline FLT3 R972/973methylation levels. Finally, combining FLT3 tyrosine kinase inhibitor PKC412 with MS023 treatment enhanced elimination of MLL-r ALL cells relative to PKC412 treatment alone in patient-derived mouse xenografts. These results indicate that abolishing FLT3 arginine methylation through PRMT1 inhibition represents a promising strategy to target MLL-r ALL cells.

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