TY - JOUR
T1 - Tumoral microenvironment prevents de novo asparagine biosynthesis in B cell lymphoma, regardless of ASNS expression
AU - Grima-Reyes, Manuel
AU - Vandenberghe, Ashaina
AU - Nemazanyy, Ivan
AU - Meola, Pauline
AU - Paul, Rachel
AU - Reverso-Meinietti, Julie
AU - Martinez-Turtos, Adriana
AU - Nottet, Nicolas
AU - Chan, Wai Kin
AU - Lorenzi, Philip L.
AU - Marchetti, Sandrine
AU - Ricci, Jean Ehrland
AU - Chiche, Johanna
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/7
Y1 - 2022/7
N2 - Depletion of circulating asparagine with l-asparaginase (ASNase) is a mainstay of leukemia treatment and is under investigation in many cancers. Expression levels of asparagine synthetase (ASNS), which catalyzes asparagine synthesis, were considered predictive of cancer cell sensitivity to ASNase treatment, a notion recently challenged. Using [U-13C5]-l-glutamine in vitro and in vivo in a mouse model of B cell lymphomas (BCLs), we demonstrated that supraphysiological or physiological concentrations of asparagine prevent de novo asparagine biosynthesis, regardless of ASNS expression levels. Overexpressing ASNS in ASNase-sensitive BCL was insufficient to confer resistance to ASNase treatment in vivo. Moreover, we showed that ASNase's glutaminase activity enables its maximal anticancer effect. Together, our results indicate that baseline ASNS expression (low or high) cannot dictate BCL dependence on de novo asparagine biosynthesis and predict BCL sensitivity to dual ASNase activity. Thus, except for ASNS-deficient cancer cells, ASNase's glutaminase activity should be considered in the clinic.
AB - Depletion of circulating asparagine with l-asparaginase (ASNase) is a mainstay of leukemia treatment and is under investigation in many cancers. Expression levels of asparagine synthetase (ASNS), which catalyzes asparagine synthesis, were considered predictive of cancer cell sensitivity to ASNase treatment, a notion recently challenged. Using [U-13C5]-l-glutamine in vitro and in vivo in a mouse model of B cell lymphomas (BCLs), we demonstrated that supraphysiological or physiological concentrations of asparagine prevent de novo asparagine biosynthesis, regardless of ASNS expression levels. Overexpressing ASNS in ASNase-sensitive BCL was insufficient to confer resistance to ASNase treatment in vivo. Moreover, we showed that ASNase's glutaminase activity enables its maximal anticancer effect. Together, our results indicate that baseline ASNS expression (low or high) cannot dictate BCL dependence on de novo asparagine biosynthesis and predict BCL sensitivity to dual ASNase activity. Thus, except for ASNS-deficient cancer cells, ASNase's glutaminase activity should be considered in the clinic.
UR - http://www.scopus.com/inward/record.url?scp=85133816843&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133816843&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abn6491
DO - 10.1126/sciadv.abn6491
M3 - Article
C2 - 35857457
AN - SCOPUS:85133816843
SN - 2375-2548
VL - 8
JO - Science Advances
JF - Science Advances
IS - 27
M1 - abn6491
ER -