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The SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia

Sofya A. Polyanskaya, Rosamaria Y. Moreno, Bin Lu, Ruopeng Feng, Yu Yao, Seema Irani, Olaf Klingbeil, Zhaolin Yang, Yiliang Wei, Osama E. Demerdash, Lukas A. Benjamin, Mitchell J. Weiss, Yan Jessie Zhang, Christopher R. Vakoc
doi: https://doi.org/10.1101/2021.05.09.443327
Sofya A. Polyanskaya
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Rosamaria Y. Moreno
2Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
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Bin Lu
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Ruopeng Feng
3Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
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Yu Yao
3Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
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Seema Irani
2Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
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Olaf Klingbeil
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Zhaolin Yang
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Yiliang Wei
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Osama E. Demerdash
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Lukas A. Benjamin
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Mitchell J. Weiss
3Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
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Yan Jessie Zhang
2Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
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Christopher R. Vakoc
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Summary

Acute myeloid leukemia (AML) cells rely on phospho-signaling pathways to gain unlimited proliferation potential. Here, we used domain-focused CRISPR screening to identify the nuclear phosphatase SCP4 as a dependency in AML, yet this enzyme is dispensable in normal hematopoietic progenitor cells. Using CRISPR exon scanning and gene complementation assays, we show that the catalytic function of SCP4 is essential in AML. Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain. We show that STK35 and PDIK1L function catalytically and redundantly in the same pathway as SCP4 to maintain AML proliferation and to support amino acid biosynthesis and transport. We provide evidence that SCP4 regulates STK35/PDIK1L through two distinct mechanisms: catalytic removal of inhibitory phosphorylation and by promoting kinase stability. Our findings reveal a phosphatase-kinase signaling complex that supports the pathogenesis of AML.

Competing Interest Statement

C.R.V. has received consulting fees from Switch, Roivant Sciences, and C4 Therapeutics, has served on the scientific advisory board of KSQ Therapeutics and Syros Pharmaceuticals, and has received research funding from Boehringer-Ingelheim during the conduct of the study.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 10, 2021.
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The SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia
Sofya A. Polyanskaya, Rosamaria Y. Moreno, Bin Lu, Ruopeng Feng, Yu Yao, Seema Irani, Olaf Klingbeil, Zhaolin Yang, Yiliang Wei, Osama E. Demerdash, Lukas A. Benjamin, Mitchell J. Weiss, Yan Jessie Zhang, Christopher R. Vakoc
bioRxiv 2021.05.09.443327; doi: https://doi.org/10.1101/2021.05.09.443327
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The SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia
Sofya A. Polyanskaya, Rosamaria Y. Moreno, Bin Lu, Ruopeng Feng, Yu Yao, Seema Irani, Olaf Klingbeil, Zhaolin Yang, Yiliang Wei, Osama E. Demerdash, Lukas A. Benjamin, Mitchell J. Weiss, Yan Jessie Zhang, Christopher R. Vakoc
bioRxiv 2021.05.09.443327; doi: https://doi.org/10.1101/2021.05.09.443327

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