TY - JOUR
T1 - Dietary thiamine influences l-asparaginase sensitivity in a subset of leukemia cells
AU - Guarecuco, Rohiverth
AU - Williams, Robert T.
AU - Baudrier, Lou
AU - La, Konnor
AU - Passarelli, Maria C.
AU - Ekizoglu, Naz
AU - Mestanoglu, Mert
AU - Alwaseem, Hanan
AU - Rostandy, Bety
AU - Fidelin, Justine
AU - Garcia-Bermudez, Javier
AU - Molina, Henrik
AU - Birsoy, Kıvanç
N1 - Publisher Copyright:
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2020/10/7
Y1 - 2020/10/7
N2 - Tumor environment influences anticancer therapy response but which extracellular nutrients affect drug sensitivity is largely unknown. Using functional genomics, we determine modifiers of l-asparaginase (ASNase) response and identify thiamine pyrophosphate kinase 1 as a metabolic dependency under ASNase treatment. While thiamine is generally not limiting for cell proliferation, a DNA-barcode competition assay identifies leukemia cell lines that grow suboptimally under low thiamine and are characterized by low expression of solute carrier family 19 member 2 (SLC19A2), a thiamine transporter. SLC19A2 is necessary for optimal growth and ASNase resistance, when standard medium thiamine is lowered ~100-fold to human plasma concentrations. In addition, humanizing blood thiamine content of mice through diet sensitizes SLC19A2-low leukemia cells to ASNase in vivo. Together, our work reveals that thiamine utilization is a determinant of ASNase response for some cancer cells and that oversupplying vitamins may affect therapeutic response in leukemia.
AB - Tumor environment influences anticancer therapy response but which extracellular nutrients affect drug sensitivity is largely unknown. Using functional genomics, we determine modifiers of l-asparaginase (ASNase) response and identify thiamine pyrophosphate kinase 1 as a metabolic dependency under ASNase treatment. While thiamine is generally not limiting for cell proliferation, a DNA-barcode competition assay identifies leukemia cell lines that grow suboptimally under low thiamine and are characterized by low expression of solute carrier family 19 member 2 (SLC19A2), a thiamine transporter. SLC19A2 is necessary for optimal growth and ASNase resistance, when standard medium thiamine is lowered ~100-fold to human plasma concentrations. In addition, humanizing blood thiamine content of mice through diet sensitizes SLC19A2-low leukemia cells to ASNase in vivo. Together, our work reveals that thiamine utilization is a determinant of ASNase response for some cancer cells and that oversupplying vitamins may affect therapeutic response in leukemia.
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U2 - 10.1126/sciadv.abc7120
DO - 10.1126/sciadv.abc7120
M3 - Article
C2 - 33036978
AN - SCOPUS:85092752443
SN - 2375-2548
VL - 6
JO - Science Advances
JF - Science Advances
IS - 41
M1 - eabc7120
ER -