Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells

H. Bhanot, M. M. Reddy, A. Nonami, E. L. Weisberg, D. Bonal, P. T. Kirschmeier, S. Salgia, K. Podar, I. Galinsky, T. K. Chowdary, D. Neuberg, G. Tonon, R. M. Stone, J. Asara, J. D. Griffin, M. Sattler

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism.

Original languageEnglish
Pages (from-to)1555-1563
Number of pages9
JournalLeukemia
Volume29
Issue number7
DOIs
Publication statusPublished - Jul 13 2015
Externally publishedYes

Fingerprint

Adenylate Kinase
Glycogen Synthase
Myeloid Leukemia
Myeloid Cells
Glycogen
Leukemia
1,4-alpha-Glucan Branching Enzyme
Uridine Diphosphate Glucose
Glucose
Metabolomics
Genomics
Pharmacology
Enzymes
Growth
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells. / Bhanot, H.; Reddy, M. M.; Nonami, A.; Weisberg, E. L.; Bonal, D.; Kirschmeier, P. T.; Salgia, S.; Podar, K.; Galinsky, I.; Chowdary, T. K.; Neuberg, D.; Tonon, G.; Stone, R. M.; Asara, J.; Griffin, J. D.; Sattler, M.

In: Leukemia, Vol. 29, No. 7, 13.07.2015, p. 1555-1563.

Research output: Contribution to journalArticle

Bhanot, H, Reddy, MM, Nonami, A, Weisberg, EL, Bonal, D, Kirschmeier, PT, Salgia, S, Podar, K, Galinsky, I, Chowdary, TK, Neuberg, D, Tonon, G, Stone, RM, Asara, J, Griffin, JD & Sattler, M 2015, 'Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells', Leukemia, vol. 29, no. 7, pp. 1555-1563. https://doi.org/10.1038/leu.2015.46
Bhanot, H. ; Reddy, M. M. ; Nonami, A. ; Weisberg, E. L. ; Bonal, D. ; Kirschmeier, P. T. ; Salgia, S. ; Podar, K. ; Galinsky, I. ; Chowdary, T. K. ; Neuberg, D. ; Tonon, G. ; Stone, R. M. ; Asara, J. ; Griffin, J. D. ; Sattler, M. / Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells. In: Leukemia. 2015 ; Vol. 29, No. 7. pp. 1555-1563.
@article{5d86a1a410594280b92cd30ac92c0e52,
title = "Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells",
abstract = "The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism.",
author = "H. Bhanot and Reddy, {M. M.} and A. Nonami and Weisberg, {E. L.} and D. Bonal and Kirschmeier, {P. T.} and S. Salgia and K. Podar and I. Galinsky and Chowdary, {T. K.} and D. Neuberg and G. Tonon and Stone, {R. M.} and J. Asara and Griffin, {J. D.} and M. Sattler",
year = "2015",
month = "7",
day = "13",
doi = "10.1038/leu.2015.46",
language = "English",
volume = "29",
pages = "1555--1563",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells

AU - Bhanot, H.

AU - Reddy, M. M.

AU - Nonami, A.

AU - Weisberg, E. L.

AU - Bonal, D.

AU - Kirschmeier, P. T.

AU - Salgia, S.

AU - Podar, K.

AU - Galinsky, I.

AU - Chowdary, T. K.

AU - Neuberg, D.

AU - Tonon, G.

AU - Stone, R. M.

AU - Asara, J.

AU - Griffin, J. D.

AU - Sattler, M.

PY - 2015/7/13

Y1 - 2015/7/13

N2 - The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism.

AB - The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism.

UR - http://www.scopus.com/inward/record.url?scp=84937022473&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937022473&partnerID=8YFLogxK

U2 - 10.1038/leu.2015.46

DO - 10.1038/leu.2015.46

M3 - Article

C2 - 25703587

AN - SCOPUS:84937022473

VL - 29

SP - 1555

EP - 1563

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 7

ER -