Authors :
Rohan Singhal
Volume/Issue :
Volume 9 - 2024, Issue 8 - August
Google Scholar :
https://tinyurl.com/3zhr2xb9
Scribd :
https://tinyurl.com/2n3xsfjd
DOI :
https://doi.org/10.38124/ijisrt/IJISRT24AUG1279
Abstract :
The “Warburg Effect” marks the metabolic
tendencies of cancer cells to primarily utilize aerobic
glycolysis over oxidative phosphorylation. However, a
comprehensive understanding of the interplay between
altered tricarboxylic acid (TCA) cycle activity and
mitochondrial dysfunction in the initiation and
progression of cancer remains elusive. Particularly in T-
cell acute lymphoblastic leukemia (T-ALL), an
aggressive hematologic malignancy derived from
immature T-cell progenitors, the role of aerobic
glycolysis in leukemogenesis warrants further
investigation. The PTEN gene is one of the most
frequently mutated/functionally-inactivated onco-
suppressors in various cancers, and PTEN mutations
account for 16% percent of all T-ALL cases. In this
research, I wanted to investigate if changes to aerobic
respiration would initiate the leukemogenesis of PTEN-
deficient T-ALL and contradict the Warburg effect,
through the removal of the citrate synthase gene, a
catalytic metabolite of the TCA cycle.
Mx1-Cre conditional knockout of citrate synthase
(CS), a catalytic metabolite of the TCA cycle, and
PTEN, an oncosuppressor often linked to T-ALL, were
employed to evaluate T-ALL in wild-type, single
knockout (PTEN -/-) and double knockout (CS -/-;
PTEN -/-) mouse models. T-ALL-related lymphocyte
concentrations were analyzed through flow cytometry
of thymus, bone marrow, blood, and spleen cell samples
bound to respective antibody cocktails, followed by
tissue composition analysis and supplemental western
blotting. Aberrant levels of T-ALL-associated
lymphocytes amongst solely PTEN-deficient samples,
yet a return to normalcy with CS deficiency, indicates
the requirement of citrate synthase for PTEN-deficient
T-ALL progression. Individual t-tests on
CD3+CD4+CD8+ cells, amongst other T-ALL-
associated lymphocytes, confirm significance in reduced
leukemogenesis (p-value < 0.01). However, analysis of
PTEN;CS-deficient myeloid cells indicates insufficient
blockade of PTEN-deficient myeloproliferative
neoplasms, presumably from impaired RBC
maintenance post-CS deletion. This research
demonstrates that the sequential context achieved via
citrate synthase deletion undermines leukemogenesis
and contrasts pre-existing ideals about the metabolic
tendencies of cancer cells, therefore implying the dual
reliance of cancer proliferation on both aerobic and
anaerobic metabolic processes.
Keywords :
Warburg Effect, Tricarboxylic Acid Cycle, T- ALL, Citrate Synthase, PTEN-Deficiency, Flow Cytometry, Leukemogenesis, Aerobic, Anaerobic, Metabolic Processes.
References :
- Martelli AM, Paganelli F, Fazio A, Bazzichetto C, Conciatori F, McCubrey JA. The Key Roles of PTEN in T-Cell Acute Lymphoblastic Leukemia Development, Progression, and Therapeutic Response. Cancers (Basel). 2019 May 6;11(5):629. doi: 10.3390/cancers11050629. PMID: 31064074; PMCID: PMC6562458.
- Jun S, Mahesula S, Mathews TP, Martin-Sandoval MS, Zhao Z, Piskounova E, Agathocleous M. The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage. Cell Metab. 2021 Sep 7;33(9):1777-1792.e8. doi: 10.1016/j.cmet.2021.07.016. Epub 2021 Aug 9. PMID: 34375613.
- Tesio M, Trinquand A, Ballerini P, Hypolite G, Lhermitte L, Petit A, Ifrah N, Baruchel A, Dombret H, Macintyre E, Asnafi V. Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia. Leukemia. 2017 Dec;31(12):2594-2600. doi: 10.1038/leu.2017.157. Epub 2017 May 25. PMID: 28539671
- Icard P, Coquerel A, Wu Z, Gligorov J, Fuks D, Fournel L, Lincet H, Simula L. Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update. Int J Mol Sci. 2021 Jun 19;22(12):6587. doi: 10.3390/ijms22126587. PMID: 34205414; PMCID: PMC8235534.
- Starkova J, Hermanova I, Hlozkova K, Hararova A, Trka J. Altered Metabolism of Leukemic Cells: New Therapeutic Opportunity. Int Rev Cell Mol Biol. 2018;336:93-147. doi: 10.1016/bs.ircmb.2017.07.012. Epub 2017 Sep 18. PMID: 29413894
The “Warburg Effect” marks the metabolic
tendencies of cancer cells to primarily utilize aerobic
glycolysis over oxidative phosphorylation. However, a
comprehensive understanding of the interplay between
altered tricarboxylic acid (TCA) cycle activity and
mitochondrial dysfunction in the initiation and
progression of cancer remains elusive. Particularly in T-
cell acute lymphoblastic leukemia (T-ALL), an
aggressive hematologic malignancy derived from
immature T-cell progenitors, the role of aerobic
glycolysis in leukemogenesis warrants further
investigation. The PTEN gene is one of the most
frequently mutated/functionally-inactivated onco-
suppressors in various cancers, and PTEN mutations
account for 16% percent of all T-ALL cases. In this
research, I wanted to investigate if changes to aerobic
respiration would initiate the leukemogenesis of PTEN-
deficient T-ALL and contradict the Warburg effect,
through the removal of the citrate synthase gene, a
catalytic metabolite of the TCA cycle.
Mx1-Cre conditional knockout of citrate synthase
(CS), a catalytic metabolite of the TCA cycle, and
PTEN, an oncosuppressor often linked to T-ALL, were
employed to evaluate T-ALL in wild-type, single
knockout (PTEN -/-) and double knockout (CS -/-;
PTEN -/-) mouse models. T-ALL-related lymphocyte
concentrations were analyzed through flow cytometry
of thymus, bone marrow, blood, and spleen cell samples
bound to respective antibody cocktails, followed by
tissue composition analysis and supplemental western
blotting. Aberrant levels of T-ALL-associated
lymphocytes amongst solely PTEN-deficient samples,
yet a return to normalcy with CS deficiency, indicates
the requirement of citrate synthase for PTEN-deficient
T-ALL progression. Individual t-tests on
CD3+CD4+CD8+ cells, amongst other T-ALL-
associated lymphocytes, confirm significance in reduced
leukemogenesis (p-value < 0.01). However, analysis of
PTEN;CS-deficient myeloid cells indicates insufficient
blockade of PTEN-deficient myeloproliferative
neoplasms, presumably from impaired RBC
maintenance post-CS deletion. This research
demonstrates that the sequential context achieved via
citrate synthase deletion undermines leukemogenesis
and contrasts pre-existing ideals about the metabolic
tendencies of cancer cells, therefore implying the dual
reliance of cancer proliferation on both aerobic and
anaerobic metabolic processes.
Keywords :
Warburg Effect, Tricarboxylic Acid Cycle, T- ALL, Citrate Synthase, PTEN-Deficiency, Flow Cytometry, Leukemogenesis, Aerobic, Anaerobic, Metabolic Processes.
