Maintenance and pharmacologic targeting of ROR1 protein levels via UHRF1 in t(1;19) pre-B-ALL

Marilynn Chow, Lina Gao, Jason D. MacManiman, Vincent T. Bicocca, Bill Chang, Joshi Alumkal, Jeffrey Tyner

Research output: Contribution to journalArticle

Abstract

Expression of the transmembrane pseudokinase ROR1 is required for survival of t(1;19)-pre-B-cell acute lymphoblastic leukemia (t(1;19) pre-B-ALL), chronic lymphocytic leukemia, and many solid tumors. However, targeting ROR1 with small-molecules has been challenging due to the absence of ROR1 kinase activity. To identify genes that regulate ROR1 expression and may, therefore, serve as surrogate drug targets, we employed an siRNA screening approach and determined that the epigenetic regulator and E3 ubiquitin ligase, UHRF1, is required for t(1;19) pre-B-ALL cell viability in a ROR1-dependent manner. Upon UHRF1 silencing, ROR1 protein is reduced without altering ROR1 mRNA, and ectopically expressed UHRF1 is sufficient to increase ROR1 levels. Additionally, proteasome inhibition rescues loss of ROR1 protein after UHRF1 silencing, suggesting a role for the proteasome in the UHRF1-ROR1 axis. Finally, we show that ROR1-positive cells are twice as sensitive to the UHRF1-targeting drug, naphthazarin, and undergo increased apoptosis compared to ROR1-negative cells. Naphthazarin elicits reduced expression of UHRF1 and ROR1, and combination of naphthazarin with inhibitors of pre-B cell receptor signaling results in further reduction of cell survival compared with either inhibitor alone. Therefore, our work reveals a mechanism by which UHRF1 stabilizes ROR1, suggesting a potential targeting strategy to inhibit ROR1 in t(1;19) pre-B-ALL and other malignancies.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalOncogene
DOIs
StateAccepted/In press - May 30 2018

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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Protein Transport
B-Lymphoid Precursor Cells
Maintenance
Proteasome Endopeptidase Complex
Pre-B Cell Receptors
Cell Survival
Ubiquitin-Protein Ligases
B-Cell Chronic Lymphocytic Leukemia
Drug Delivery Systems
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Epigenomics
Small Interfering RNA
Neoplasms
Proteins
Phosphotransferases
Apoptosis
Messenger RNA
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Maintenance and pharmacologic targeting of ROR1 protein levels via UHRF1 in t(1;19) pre-B-ALL. / Chow, Marilynn; Gao, Lina; MacManiman, Jason D.; Bicocca, Vincent T.; Chang, Bill; Alumkal, Joshi; Tyner, Jeffrey.

In: Oncogene, 30.05.2018, p. 1-12.

Research output: Contribution to journalArticle

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