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Unknown function of the known steroid hormone in targeting cancer stem cells in Myeloid leukaemia (ML): Progesterone (P4), a steroid hormone, inhibits cytosolic aminotransferase BCAT1 expression, increases a-ketoglutarate levels, promotes degradation of HIF1a levels, increases DNA demethylase levels, promotes hypomethylation, increases the expression of tumor suppressor genes, inhibits leukaemia-initiating potential of AML cells, promotes differentiation of AML cells, and inhibits cancer progression in AML via up-regulation of its target gene, 18/August/2017, 12.31 am

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Introduction to what they say:

A study from the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; and German Cancer Consortium (DKTK), DKFZ, 69120 Heidelberg, Germany shows that “BCAT1 restricts aKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation”. This study was published, in the 16 November 2017 issue of the journal “Nature” [One of the best journals in General Science with an I.F of 43 plus], by Prof. Trumpp, Simon Raffel, and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Unknown function of the known steroid hormone in targeting cancer stem cells in Myeloid leukaemia (ML): Progesterone (P4), a steroid hormone, inhibits cytosolic aminotransferase BCAT1 expression, increases a-ketoglutarate levels, promotes degradation of HIF1a levels, increases DNA demethylase levels, promotes hypomethylation, increases the expression of tumor suppressor genes, inhibits leukaemia-initiating potential of AML cells, promotes differentiation of AML cells, and inhibits cancer progression in AML via up-regulation of its target gene


From Significance of the study to Public health relevance:

Given that: (i) each year nearly 14 million people are diagnosed with cancer globally, and little more than half of them cannot be cured by current treatment methodologies (and hence they will die); (ii) cancer deaths globally are expected to be doubled by next decade or so; (iii) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide; (iv) Acute myeloid leukemia (AML) is one of the most predominant leukemias among all adult leukemias, while Chronic myeloid leukemia (CML) accounts for about little less than 10% of all leukemias; (v) each year about 10,500 and 2900 new cases of AML are reported in the US and the UK, respectively; (vi) cure rates of AML ranges from 20-45% only, there is an urgent need to find: (i) a way to inhibit leukaemia-initiating potential of AML stem cells; (ii) activate patient’s own immune system (Cancer immunotherapy); (iii) target proteins that drug resistance during treatment; (iv) prevent disease relapse after conventional cancer therapy; (v) a cheaper alternative to the existing expensive anticancer drugs; (vi) a side-effect-free natural product-based drug; and (vii) a way to effectively treat and prevent metastatic progression and relapse of cancers.


What is known:

Prof.Trumpp and his research team members and others have recently shown that: (1) the cytosolic aminotransferase BCAT1 (branched-chain amino acid (BCAA) transaminase 1) is upregulated in human acute myeloid leukaemia (AML) stem-cells; (2) BCAT1 promotes homeostasis of tricarboxylic acid cycle component a-ketoglutarate (aKG); (3) deletion of BCAT1 in leukemic cells results in accumulation of aKG; (4) aKG, which is accumulated in BCAT1-deleted leukemic cells, promotes degradation of HIF1a, resulting in abrogation of leukaemia-initiating potential; (5) overexpression of BCAT1 in leukaemia cells results in (a) decreaed levels of aKG; (b) altered TET DNA demethylase; and (c) DNA hypermethylation; and (6) high levels of BCAT1 in leukaemic cells matches with a) shorter survival; and b) disease relapse, suggesting that suppression of BCAT1 in leukemic cells may (a) increase aKG levels; (b) increase DNA demethylase levels; and promote hypomethylation; (c) promote EGLN1-mediated degradation of HIF1a; (d) attenuate leukaemia-initiating potential of cancer cells; (d) promote survival; and (e) prevent disease relapse in patients with IDH(wt)TET2(wt) AML.


From research findings to therapeutic opportunity :

This study suggests a steroid hormone-derived anticancer therapy for IDH(wt)TET2(wt) AML. Progesterone (P4), by increasing the expression of its target genes, it may decrease the expression of BCAT1 and other genes (fig. 1). Thereby, it may: (i) increase the levels of aKG; (ii) promote degradation of HIF1a; (iii) alter TET DNA demethylase levels; (iv) promote DNA hypomethylation; (v) decrease the expression of oncogenic MiRs; (vi) increase the expression of tumor suppressor genes; (vii) inhibit leukaemia-initiating potential of AML stem cells; (viii) decrease BCAA (Branched-chain amino acid) production; (ix) promote differentiation of leukemic cells; (x) slow down CML and de novo acute myeloid leukaemia (AML) growth; and (vi) inhibit cancer progression in Myeloid leukemia (fig.1).

Figure 1. Mechanistic insights into how Progesterone (P4) suppresses the expression of BCAT1 and HIF1a to inhibit cancer progression in myeloid leukemia

Figure 2. Progesterone (P4) functions as an anti-cancer agent in ML.

 

Thus, pharmacological formulations encompassing “Progesterone (P4) or its analogs, either alone or in combination with other known anti-cancer drugs,” may be used to inhibit leukemia stem-cell function and slow down cancer proliferation in patients with IDH(wt)TET2(wt) AML.


Details of the Research findings:

Idea Proposed/Formulated (with experimental evidence) by Dr L Boominathan Ph.D.

Amount: $1, 500#

Undisclosed mechanistic information: How does Progesterone (P4) decrease the expression of BCAT1 and HIF1α to inhibit leukemia-initiating potential of AML stem cells?

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References:

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Citation: Boominathan, L., Unknown function of the known steroid hormone in targeting cancer stem cells in Myeloid leukaemia (ML): Progesterone (P4), a steroid hormone, inhibits cytosolic aminotransferase BCAT1 expression, increases a-ketoglutarate levels, promotes degradation of HIF1a levels, increases DNA demethylase levels, promotes hypomethylation, increases the expression of tumor suppressor genes, inhibits leukaemia-initiating potential of AML cells, promotes differentiation of AML cells, and inhibits cancer progression in AML via up-regulation of its target gene, 18/August/2017, 12.30 am, Genome-2-BioMedicine Discovery center (GBMD), http://genomediscovery.org

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