Metabolism, Stem Cells, and Their Effects on Acute Myeloid - - PowerPoint PPT Presentation

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Metabolism, Stem Cells, and Their Effects on Acute Myeloid - - PowerPoint PPT Presentation

Dec 08, 2022 276 likes •679 views

Metabolism, Stem Cells, and Their Effects on Acute Myeloid Leukemia By: Colin Dominick, Cecilie Elliott, Murrie Grimes, Katy Kosiorek, Rana Haboush, and Teddy Gutches Agenda Background information: General terminology, leukemia,

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Metabolism, Stem Cells, and Their Effects on Acute Myeloid Leukemia

By: Colin Dominick, Cecilie Elliott, Murrie Grimes, Katy Kosiorek, Rana Haboush, and Teddy Gutches

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Agenda

  • Background information:

○ General terminology, leukemia, and

  • ther supporting information
  • Paper

○ Specific aim, figures, conclusions, and

  • ther relevant findings
  • Discussion
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Discussion Question:

  • What are your thoughts on this paper?

○ What they did well (pros) ○ What you are confused about (cons)

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Discussion Question:

What do you remember on last week’s discussion about stem cells?

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What is Cancer?

  • Malignant growth of cells that may arise from a mutation, translocation

event, or an overexpression of a gene

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Hallmarks of Cancer

Figure 1.

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Emerging Hallmarks of Cancer

  • Evading immune

destruction

  • Deregulating cellular

energetics

Figure 3.

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What is Leukemia?

  • Begins in blood stem cells
  • Myeloid or lymphoid
  • Acute or chronic
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Types of Leukemia

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Acute Myeloid Leukemia

Cancer that begins in the soft bone marrow Spreads quickly (acute)

  • Blood
  • Lymph nodes
  • Liver and spleen
  • Central nervous system
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What Drives AML?

  • Malignant transformation
  • Glycolysis
  • Mitochondrial oxidative phosphorylation
  • Translocation event causes a gene fusion of HOXA9 and NUP98
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Glutamine and Cell Growth

  • Glutamine is a large

source of energy for cell proliferation (2009)

Figure 2b.

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Glycolysis

Glucose → Pyruvate

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Oxidative Phosphorylation

NADH & FADH2 → ATP

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Cancer Cell Metabolism

  • What is changing during malignancy?

○ Rate changes in metabolism

  • The Warburg Effect

○ Aerobic Glycolysis ○ Glycolytic dependency

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Specific Aim

1. Uncover a novel function for JMJD1C, independent of it’s already known H3K9 demethylase function. 2. Discover a novel treatment for AML by targeting the energy production pathways of glycolysis and oxidative phosphorylation (OXPHOS).

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Let’s dive into our paper!

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Figure 1. The metabolism-associated domain is required for JMJDC1 to promote leukemogenesis in vivo in HOXA9-dependent AML.

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Figure 1. Continued...

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Discussion Question:

Talk amongst your table!

  • What does Figure 1 suggest about the potential functions of

JMJD1C?

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Figure 2. JMJD1C modulates bioenergetics through upregulation of genes/pathways involved in metabolic processes in HOXA/MEIS1 AML.

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Figure 2. Continued...

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Discussion Question:

  • In what ways could you

inhibit the dimerization of PKM2 or stop the dimer from functioning properly?

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Figure 3. Inhibition of dimeric p-PKM2 by Shik suppresses glycolysis leading to a preferential use of OXPHOS over glycolysis for ATP production in an origin-specific manner.

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Figure 3. Continued...

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Discussion Question:

Talk amongst your table!

  • Why was the ATP concentration result not significant between

the Shik treatment and the DMSO?

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Figure 4. Co-suppression of glycolysis and OXPHOS by Shik and ABT-263 reduces ATP production impairing MLL-AF9 LSCs.

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Figure 4. Continued…

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Discussion Question:

Talk amongst your table!

  • Why does the co-suppression of glycolysis and OXPHOS

impair MLL-AF9 LSCs?

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Discussion Question:

Talk amongst your table!

  • What does the overexpression of HOXA9 mean for your cancer

prognosis, and how does JMJD1C play a role in its expression?

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Figure 5. In vivo treatment with Shik ad ABT-263 reduces tumor burden in AML PDX mice.

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Figure 5. Continued...

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Conclusions

  • JMJD1C role
  • HOXA9 relation
  • The Warburg Effect
  • Drug response
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Future Directions

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Discussion Questions:

1. Why was JMJD1C important in regulating cancer metabolism? 2. Which figure is most important? 3. What are the limitations? 4. How would you improve this work? 5. How would this work contribute to cancer biology?

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References

1. Lynch JR. JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent

  • leukemogenesis. Springer Nature. 2019; 1-11.

2. Gao P., Tchernyshyov, I., Chang, TC., Lee, YS., Kita, K., Ochi, T., Zeller, K., De Marzo, AM., Van Eyk, J., Mendelle, J. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009. 762-765. 3. Hanahan D., Weinberg, R. A. Hallmarks of Cancer: The Next Generation. Cell. 2011. 646-674.