RT Journal Article
T1 Targeting sphingosine kinase isoforms effectively reduces growth and survival of neoplastic mast cells with D816V-KIT
A1 Bandara, Geethani
A1 Muñoz-Cano, Rosa
A1 Tobío Ageitos, Araceli
A1 Yin, Yuzhi
A1 Komarow, Hirsh D.
A1 Desai, Avanti
A1 Metcalfe, Dean D.
A1 Olivera, Ana
K1 Sphingosine kinase
K1 Sphingosine kinase inhibitor
K1 Sphingosine-1-phosphate
K1 Mastocytosis
K1 D816V
K1 KIT
K1 Mast cells
AB Mastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues  that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor  for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis  are limited, thus exploration of novel pharmacological targets that reduce MC burden is  desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate  (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the  involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth. While SPHK2 inhibition prevented entry into the cell cycle in  normal and neoplastic human MCs with minimal effect on cell survival, SPHK1 inhibition  caused cell cycle arrest in G2/M and apoptosis, particularly in D816V-KIT MCs. This  was mediated via activation of the DNA damage response (DDR) cascade, including  phosphorylation of the checkpoint kinase 2 (CHK2), CHK2-mediated M-phase inducer  phosphatase 3 depletion, and p53 activation. Combination treatment of SPHK inhibitors  with KIT inhibitors showed greater growth inhibition of D816V-KIT MCs than either inhibitor  alone. Furthermore, inhibition of SPHK isoforms reduced the number of malignant  bone marrow MCs from patients with mastocytosis and the growth of D816V-KIT MCs in  a xenograft mouse model. Our results reveal a role for SPHK isoforms in the regulation of  growth and survival in normal and neoplastic MCs and suggest a regulatory function for  SPHK1 in the DDR in MCs with KIT mutations. The findings also suggest that targeting  the SPHK/S1P axis may provide an alternative to tyrosine kinase inhibitors, alone or  in combination, for the treatment of aggressive mastocytosis and other hematological  malignancies associated with the D816V-KIT mutation.
PB Frontiers
YR 2018
FD 2018-03-28
LK http://hdl.handle.net/10347/20453
UL http://hdl.handle.net/10347/20453
LA eng
NO Bandara G, Muñoz-Cano R, Tobío A, Yin Y, Komarow HD, Desai A, Metcalfe DD and Olivera A (2018) Targeting Sphingosine Kinase Isoforms Effectively Reduces Growth and Survival of Neoplastic Mast Cells With D816V-KIT. Front. Immunol. 9:631. doi: 10.3389/fimmu.2018.00631
NO This work was supported by the Division of Intramural ResearchPrograms within NIAID, at the National Institutes of Health.RM-C belongs to the Spanish Research Network ARADyALRD16/0006/0007 of the Carlos III Health Institute and is arecipient of a Juan Rodes fellowship (Carlos II Health InstituteJR16/00016)
DS Minerva
RD 28 abr 2026