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Tcof1 haploinsufficiency promotes early T cell precursor-like leukemia in NrasQ61R/+ mice

Leukemia volume 36, pages 1167–1170 (2022)Cite this article

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T-cell acute lymphoblastic leukemia (T-ALL) is a malignant neoplasm of transformed immature T-cells [1]. Recently, a refractory subset of T-ALL derived from the early T-cell precursors (ETPs) has been recognized and designated as ETP-ALL [2, 3]. ETP-ALL represents ~12% of T-ALL in children and 7.4% in adults, and confers a significantly worse outcome than other T-ALL subtypes (non-ETP T-ALL) [2]. ETP-ALL is characterized by distinct phenotypes, including simultaneous expression of myeloid or stem cell markers [2] and prevalent activating mutations in the Ras signaling pathway (e.g., NRAS and KRAS), which are rarely identified in non-ETP T-ALL but characteristic for myeloid leukemias [3].

Oncogenic RAS mutations predominantly occur at G12, G13, or Q61 codons, which compromise their GTPase activity and result in the accumulation of GTP-bound active Ras and hyperactivation of Ras downstream signaling [4]. In addition to the prevalent NRAS and KRAS mutations in ETP-ALL, we found concurrent oncogenic RAS mutations and haploinsufficiency of WT KRAS in some ETP-ALL patients. Notably, Kras−/−; NrasQ61R/+ mice developed early onset of T-cell malignancy that is characteristic of human ETP-ALL [5]. We showed that Kras−/− and NrasQ61R signaling cooperate to downregulate expression of Rasgrp1, a Ras guanine exchange factor [6]. Rasgrp1 downregulation leads to hyperactivation of Nras/ERK signaling, T cell proliferation, and expansion of the ETP compartment. However, it remains unclear if Rasgrp1 downregulation drives ETP-like ALL formation in NrasQ61R/+ mice.

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Fig. 1: Quantitative phospho-proteomics and RNA-Seq analyses identify Tcof1 as a potential regulator of Kras−/−; NrasQ61R/+-induced ETP-like leukemia.
Fig. 2: Tcof1 haploinsufficiency promotes expansion of early T-cell precursors and an early on-set of ETP-like ALL in NrasQ61R/+ mice.

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Acknowledgements

We would like to thank the University of Wisconsin Carbone Comprehensive Cancer Center (UWCCC) for use of its Shared Services (Flow Cytometry Laboratory, Transgenic Animal Facility, and Experimental Pathology Laboratory) to complete this research.

Funding

This work was supported by the startup funding from the Marshfield Clinic Research Foundation to ZW, NIH grant P41 GM108538 to AH and JJC, NIH grant R01DE13172 to LL and RS, NIH grants R01CA187318 and R01HL120724 to JPR, NIH grants R01AI079087 and R01HL130724 to DW, and NIH grant R01CA152108 and DoD Impact Award W81XWH-20-1-0616 to JZ. This work was also supported in part by NIH/NCI P30 CA014520--UW Comprehensive Cancer Center Support.

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Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, 53705, USA

    Zhi Wen, Remington Finn, Xin Gao, Yun Zhou, Grant Yun & Jing Zhang

  2. Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield Clinic Health System, Marshfield, WI, 54449, USA

    Zhi Wen

  3. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Lin Li & Rita Shiang

  4. National Center for Quantitative Biology of Complex Systems, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Alexander Hebert & Joshua J. Coon

  5. Department of Pathology & Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, Madison, WI, 53792, USA

    Erik A. Ranheim

  6. Department of Anatomy, University of California-San Francisco, San Francisco, CA, 94143, USA

    Jeroen P. Roose

  7. Department of Biomolecular Chemistry and Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Joshua J. Coon

  8. Morgridge Institute for Research, Madison, WI, 53706, USA

    Joshua J. Coon

  9. Blood Research Institute, Versiti, Milwaukee, WI, 53226, USA

    Renren Wen & Demin Wang

  10. Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Menggang Yu

  11. Wisconsin Blood Cancer Research Institute, University of Wisconsin-Madison, Madison, WI, 53705, USA

    Jing Zhang

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  1. Zhi Wen
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Contributions

Conception and design: ZW, DW, and JZ. Acquisition of cell line and mouse data: ZW, RF and GY. Analysis and interpretation of cell line and mouse data: ZW, XG, EAR, MYu, DW, and JZ. Acquisition and analysis of proteomic and phosphor-proteomic data: AH, JJC. Writing, review, and/or revision of the manuscript: ZW, XG, AH, EAR, JJC, RS, RW, DW, and JZ. Technical or material support: LL, YZ. Study supervision: JZ.

Corresponding authors

Correspondence to Demin Wang or Jing Zhang.

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Wen, Z., Finn, R., Gao, X. et al. Tcof1 haploinsufficiency promotes early T cell precursor-like leukemia in NrasQ61R/+ mice. Leukemia 36, 1167–1170 (2022). https://doi.org/10.1038/s41375-022-01510-7

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