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Investigating diet to control asparagine uptake as an adjunct to asparaginase treatment

ABSTRACT:

Refinements of multidrug regimens, and particularly the addition of L-asparaginase, resulted in an immediate gain in survival for pediatric acute lymphoblastic leukemia patients. Yet L-asparaginase has substantial side effects which may require dose reductions or delays in subsequent doses. There are at least 3 possible sources of L-asparagine to consider when balancing blood levels with asparaginase dosing, the diet, cell synthesis and bacterial synthesis. To date, there is one precedent in which blood L-asparagine levels are reduced in parallel with a reduction in consumed levels, in mice. We build on that approach in experiments aimed at testing whether a long-term dietary restriction of L-asparagine (Asn) can impact blood levels and possibly enhance L-asparaginase efficacy. In our experiment, 2 groups of mice received food pellets either with 4% or 0% Asn. Blood and fecal metabolites and fecal bacteria were sampled over 72 days. After this accommodation period, all mice continued their diet and received a single injection of pegylated E. coli recombinant L-asparaginase (P-ASP). Samples for bacteria and metabolites were collected 4 and 5 days later, respectively. Neither diet had adverse effects on the general health of the mice nor did diet alone change blood Asn levels. Both diets led to changes in gut bacteria. P-ASP depleted blood Asn in mice consuming either diet. Bacteria identified in fecal pellets revealed that the microbiomes of mice in the 2 cages were different (cage effect) and remained different. Metagenomic analyses of day 72 stool indicated there were no diet-dependent differences in bacterial asparaginase and asparagine synthetase. Further research should confirm these results, as well as include approaches to determine the source of Asn in the blood while ingesting diets with no/low or high amounts of Asn

INSTRUMENT(S): Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13764 | MetaboLights | 2026-01-25

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13764_LC-MS_positive_reverse-phase_metabolite_profiling (1).txt	Txt
	a_MTBLS13764_LC-MS_positive_reverse-phase_metabolite_profiling (2).txt	Txt
	a_MTBLS13764_LC-MS_positive_reverse-phase_metabolite_profiling .txt	Txt
	a_MTBLS13764_LC-MS_positive_reverse-phase_metabolite_profiling-1 (1).txt	Txt
	a_MTBLS13764_LC-MS_positive_reverse-phase_metabolite_profiling-1 copy.txt	Txt

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Project description:Osteolytic lesions with suppression of osteoblastic (OB) differentiation are hallmarks of multiple myeloma (MM). Most recently, Gln availability has been found to be essential to sustain bone mass formation in murine models. On the other hand, MM cells are Gln-addicted and consume huge amounts of the amino acid, leading to a partial Gln depletion in the bone marrow (BM) plasma. We hypothesize that MM-dependent Gln depletion contributes to the defective OB differentiation characteristic of MM. Conversely, GLS (both KGA and GAC isoforms) and SLC38A2, the gene for the concentrative Gln transporter SNAT2, were induced. Consistent with this conclusion, the activity of SNAT2 was absent in undifferentiated hMSCs but well detectable after 14 days of OB differentiation, when total Gln uptake was also increased. Under the same conditions, OB differentiation markers (RUNX2, COL1A1, ALPL expression and ALPL activity or staining) were significantly induced but their expression was blunted by incubation in low-Gln (0.4 mM) medium or in the presence of the SNAT2 inhibitor MeAIB. The incubation in Gln-free D-MEM suppressed the induction of GLS and SLC38A2 along with OB differentiation, which was restored by the supplementation of Non-Essential Amino Acids (NEAA). Among NEAA, only asparagine (Asn) was able to rescue OB differentiation in the absence of Gln. The determination of intracellular amino acids with MS indicated that OB differentiation was associated with the increase of cell Asn, without significant changes of Gln, glutamate (Glu) or aspartate (Asp). Asparagine Synthetase (ASNS), the Gln-dependent enzyme that accounts for Asn synthesis, was also found induced during OB differentiation of hMSCs. Gene Expression Profiles of primary BM hMSCs and OBs from bone biopsies of both healthy donors and MM patients indicated that GLS, ASNS, and SLC38A2 are more expressed in OBs, while the expression of GLUL, the gene for GS, is higher in undifferentiated hMSCs from healthy donors. Overall, these results indicate that (1) OB differentiation of hMSCs is Gln-dependent; (2) the partial Gln depletion, imposed by Gln-addicted MM cells in the BM microenvironment, contributes to the impairment of osteoblastic differentiation of hMSCs; (3) hindrance of differentiation may depend on the limited availability of intracellular Asn derived from Gln-dependent ASNS. These results support the evidence that Gln addiction of MM cells affects bone microenvironment leading to the inhibition of OB differentiation and, consequently, to the development of MM bone disease.

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Investigating diet to control asparagine uptake as an adjunct to asparaginase treatment

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