Integrating a prospective pilot trial and patient-derived xenografts to trace metabolic changes associated with acute myeloid leukemia

Abstract

Despite the considerable progress in understanding the molecular bases of acute myeloid leukemia (AML), new tools to link disease biology to the unpredictable patient clinical course are still needed. Herein, high-throughput metabolomics, combined with the other “-omics” disciplines, holds promise in identifying disease-specific and clinically relevant features.In this study, we took advantage of nuclear magnetic resonance (NMR) to trace AML-associated metabolic trajectory employing two complementary strategies. On the one hand, we performed a prospective observational clinical trial to identify metabolic changes associated with blast clearance during the first two cycles of intensive chemotherapy in nine adult patients. On the other hand, to reduce the intrinsic variability associated with human samples and AML genetic heterogeneity, we analyzed the metabolic changes in the plasma of immunocompromised mice upon engraftment of primary human AML blasts.Combining the two longitudinal approaches, we narrowed our screen to seven common metabolites, for which we observed a mirror-like trajectory in mice and humans, tracing AML progression and remission, respectively. We interpreted this set of metabolites as a dynamic fingerprint of AML evolution.Overall, these NMR-based metabolomic data, to be consolidated in larger cohorts and integrated in more comprehensive system biology approaches, hold promise for providing valuable and non-redundant information on the systemic effects of leukemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0346-2) contains supplementary material, which is available to authorized users.

Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations

“… 95 , 166 , 190 , 191 , 192 , 193 , 194 , 195 JJ012 and CS1 have been successfully propagated in mice. 194 For AML, it has been common to use human primary AML cells, either as grafts in mice 196 or cultured cells. 197 , 198 Transfected commercially available mutIDH1 cell lines have also been established (HL60 with mutIDH1 R132H ).…”

Metabolomics analysis of salvage chemotherapy on refractory acute myeloid leukemia patients

“…31,39,40 In the present study, we took advantage of an established non-targeted metabolomic proling platform that combined UPLC/MS/MS with GC/MS, a total of 390 named metabolites were identied in the tested 20 samples, which uncovered so far the broadest serum metabolome for acute leukemia patients as compared with previous studies. 38,[41][42][43][44][45][46][47] Moreover, those 390 metabolites were mapped to 8 super-pathways and 71 sub-pathways. Obviously, most of the central metabolic pathways were included among the identied metabolites and we believed this nontargeted metabolomic proling platform successfully elucidated the serum metabolome for RAML patients.…”

Differentiation and prognostic stratification of acute myeloid leukemia by serum‐based spectroscopy coupling with metabolic fingerprints

“…Indicators of either Raman shift (e.g., SERS) or chemical shift (e.g., NMR) have the ability to fingerprint chemical groups or small molecular weight metabolites, while both have exhibited substantial prospect due to exquisite molecular specificity and minimal interference of all kinds of biological samples. Plenty of evidence have proven to facilitate the whole detection procedure and meanwhile help to take detection of samples beyond cell down to molecular level 7–9 . During the last decade, considerable efforts have been paid on the characterization of specific components within specimens, and the characteristics of specific nanomaterial‐based SERS probe that can assemble on the surface of the components 10,11 .…”

“…Plenty of evidence have proven to facilitate the whole detection procedure and meanwhile help to take detection of samples beyond cell down to molecular level. [7][8][9] During the last decade, considerable efforts have been paid on the characterization of specific components within specimens, and the characteristics of specific nanomaterial-based SERS probe that can assemble on the surface of the components. 10,11 Notably, the results may suggest vibrational alterations derived from small molecular weight metabolites, but it is not comprehensive and the types are limited.…”