The thrombopoietin mimetic JNJ-26366821 increases megakaryopoiesis without affecting malignant myeloid proliferation

Diego Adrianzen-Herrera, Gaurav Choudhary, Shanisha Gordon-Mitchell, Nandini Ramachandra, Tushar D. Bhagat, Hui Zhang, Srinivas Aluri, Aditi Shastri, Ulrich G. Steidl, Britta Will, Weng Lang Yang, Michelle Mahler, Gary Eichenbaum, Chandan Guha, Amit Verma

Research output: Contribution to journalArticle

Abstract

Thrombocytopenia remains a challenge in myeloid malignancies, needing safer and more effective therapies. JNJ-26366821, a pegylated synthetic peptide thrombopoietin (TPO) mimetic not homologous to endogenous TPO, has an in-vitro EC50 of 0.2 ng/mL for the TPO receptor and dose dependently elevates platelets in volunteers. We demonstrate that JNJ-26366821 increases megakaryocytic differentiation and megakaryocytic colony formation in healthy controls and samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). JNJ-26366821 had no effect on proliferation of malignant myeloid cell lines at doses up to 1000 ng/mL and malignant patient-derived mononuclear cells showed no increased cell growth or leukemic colony formation capacity at concentrations between 0.2 ng/mL and 10 ng/mL. Furthermore, JNJ-26366821 did not enhance in-vivo engraftment of leukemic cells in an AML xenotransplantation murine model. Our results show that JNJ-26366821 stimulates megakaryopoiesis without causing proliferation of the malignant myeloid clones in MDS/AML and provides the rationale for clinical testing of JNJ-26366821 in myeloid malignancies.

Original languageEnglish (US)
JournalLeukemia and Lymphoma
DOIs
StateAccepted/In press - 2020

Keywords

  • acute myeloid leukemia
  • JNJ-26366821
  • myelodysplastic syndrome
  • platelets
  • Thrombopoietin

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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