Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response.

Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.

[1]  N. Socci,et al.  Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. , 2012, The New England journal of medicine.

[2]  M. S. van der Knaap,et al.  Progress in understanding 2-hydroxyglutaric acidurias , 2012, Journal of Inherited Metabolic Disease.

[3]  Jeffrey W. Clark,et al.  Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. , 2012, The oncologist.

[4]  A. Emadi.  At the Crossroads: Tumor Metabolism and Epigenetics , 2011, Science Translational Medicine.

[5]  R. Klose,et al.  The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases , 2011, EMBO reports.

[6]  T. Haferlach,et al.  IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. , 2010, Blood.

[7]  J. Licht,et al.  Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. , 2010, Cancer cell.

[8]  T. Haferlach,et al.  IDH Mutations Can Be Detected In 28.7% of All Normal Karyotype AML and Have Unfavourable Impact on the NPM1+/FLT3-ITD- Genotype , 2010 .

[9]  R. Hills,et al.  The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. , 2010, Blood.

[10]  W. van Putten,et al.  Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. , 2010, Blood.

[11]  Yi Zhang,et al.  Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification , 2010, Nature.

[12]  H. Dombret,et al.  Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Manuela Zucknick,et al.  IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Hai Yan,et al.  Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. , 2010, Journal of the National Cancer Institute.

[15]  M. Caligiuri,et al.  IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  Hai Yan,et al.  IDH1 and IDH2: not your typical oncogenes. , 2010, Cancer cell.

[17]  Omar Abdel-Wahab,et al.  The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. , 2010, Cancer cell.

[18]  Tak W. Mak,et al.  Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations , 2010, The Journal of experimental medicine.

[19]  E. Gottlieb,et al.  IDH1 mutations in gliomas: when an enzyme loses its grip. , 2010, Cancer cell.

[20]  L. Liau,et al.  Cancer-associated IDH1 mutations produce 2-hydroxyglutarate , 2009, Nature.

[21]  Ken Chen,et al.  Recurring mutations found by sequencing an acute myeloid leukemia genome. , 2009, The New England journal of medicine.

[22]  David R. Liu,et al.  Conversion of 5-Methylcytosine to 5- Hydroxymethylcytosine in Mammalian DNA by the MLL Partner TET1 , 2009 .

[23]  F. Ducray,et al.  IDH1 and IDH2 mutations in gliomas. , 2009, The New England journal of medicine.

[24]  E. Schaftingen,et al.  l-2-Hydroxyglutaric aciduria, a disorder of metabolite repair , 2009, Journal of Inherited Metabolic Disease.

[25]  Joshua D. Rabinowitz,et al.  A high-performance liquid chromatography-tandem mass spectrometry method for quantitation of nitrogen-containing intracellular metabolites , 2006, Journal of the American Society for Mass Spectrometry.