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Panobinostat inhibits the proliferation of CD34 + CD38 − cells under stimulation of hematopoietic growth factors on AGM‐S3 cells in juvenile myelomonocytic leukemia
Author(s) -
Kurata Takashi,
Matsuda Kazuyuki,
Hirabayashi Koichi,
Shigemura Tomonari,
Sakashita Kazuo,
Nakahata Tatsutoshi,
Koike Kenichi
Publication year - 2018
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.27261
Subject(s) - panobinostat , juvenile myelomonocytic leukemia , cancer research , cd34 , cd38 , haematopoiesis , stem cell , leukemia , medicine , immunology , biology , microbiology and biotechnology , histone deacetylase , biochemistry , histone , gene
Background Encouraging responses to histone deacetylase inhibitors have been reported for hematologic malignancies. Here, we report effects of panobinostat and 5‐azacytidine on the proliferation of juvenile myelomonocytic leukemia (JMML) CD34 + cells. Procedure We previously reported that stimulation of JMML CD34 + cells with stem cell factor and thrombopoietin on irradiated murine AGM‐S3 cells led to substantial expansion of JMML CD34 + cells that contained leukemic stem cells capable of transplantation into immunodeficient mice. Using this culture system, we evaluated effects of panobinostat and 5‐azacytidine on the proliferation of JMML CD34 + cells. Results Panobinostat dose dependently reduced the numbers of day 7 CD34 + cells generated under stimulation of hematopoietic growth factors on AGM‐S3 cells in all eight patients with JMML. These patients possessed various genetic and/or karyotypic abnormalities. CD34 + CD38 − cells were substantially more sensitive to panobinostat at 10 and 20 nM than CD34 + CD38 + cells. Panobinostat, however, failed to influence the ability of AGM‐S3 cells to stimulate JMML CD34 + cell production. In contrast to HL60 cells, apoptosis and cell cycle arrest in panobinostat‐mediated inhibition were at low levels in JMML. The inhibitor also suppressed the factor‐dependent proliferation of normal CD34 + cells on AGM‐S3 cells. Meanwhile, no substantial inhibitory effects of 5‐azacytidine on the growth of JMML CD34 + cells were observed. Conclusions These results demonstrate that panobinostat directly suppresses the growth of JMML CD34 + cells, in particular CD34 + CD38 − cells, regardless of the genetic abnormality type, suggesting that it is a useful antileukemic drug to target JMML stem cells at a pretransplant stage.