TY - JOUR
T1 - The thrombopoietin mimetic JNJ-26366821 increases megakaryopoiesis without affecting malignant myeloid proliferation
AU - Adrianzen-Herrera, Diego
AU - Choudhary, Gaurav
AU - Gordon-Mitchell, Shanisha
AU - Ramachandra, Nandini
AU - Bhagat, Tushar
AU - Zhang, Hui
AU - Aluri, Srinivas
AU - Shastri, Aditi
AU - Steidl, Ulrich
AU - Will, Britta
AU - Yang, Weng Lang
AU - Mahler, Michelle
AU - Eichenbaum, Gary
AU - Guha, Chandan
AU - Verma, Amit
N1 - Publisher Copyright:
© 2020 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2020/8/23
Y1 - 2020/8/23
N2 - 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.
AB - 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.
KW - JNJ-26366821
KW - Thrombopoietin
KW - acute myeloid leukemia
KW - myelodysplastic syndrome
KW - platelets
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UR - http://www.scopus.com/inward/citedby.url?scp=85087422506&partnerID=8YFLogxK
U2 - 10.1080/10428194.2020.1775213
DO - 10.1080/10428194.2020.1775213
M3 - Article
C2 - 32578476
AN - SCOPUS:85087422506
SN - 1042-8194
VL - 61
SP - 2453
EP - 2465
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 10
ER -