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Acute Myeloid Leukemia: Spotlight on the FLT3/ITD Mutation

My topic for the Capstone Project is acute myeloid leukemia (AML) and I decided to focus on the FLT3-ITD mutation. FLT3 is a tyrosine kinase receptor and ITD refers to a an internal tandem duplication mutation1,2. I decided to narrow my search to this particular mutation because the presence of FLT3/ITD is a major factor for predicting disease free survival and relapse rates in AML3. FLT3/ITD mutations in AML tend to be more aggressive cancers and less responsive to standard treatments, so I thought this would be an interesting subset of AML to study.

The first category I had chosen is AML characteristics and causes. Here, I would describe the cellular changes that occur when this subset of leukemia arises and the characteristics that are needed for an AML diagnosis. Leukemia arises from stem cells in the bone marrow. The diagnosis of AML requires a bone marrow biopsy and cytology report to determine the number of blast cells in the blood as well as any chromosomal abnormalities that have arisen. What has been evolving in the literature is the exact categorization of AML and the discovery of various chromosomal mutations that are associated with it. I thought it would be crucial to describe what AML is before jumping right into the particular mutation I am focusing on.

The next category is FLT3 categorization-so, structurally defining what FLT3 is and its role in bone marrow cells. FLT3 has a role in hematopoietic growth factors by stimulating the growth of bone marrow cells alone and in combination with other hematopoietic growth factors. Current literature is uncovering various pathways involved with growth signaling that are also impacted by FLT3. It seems logical that mutating FLT3 can have an impact on cells becoming cancerous by interfering with the typical growth signals.

Next, I would categorize the FLT3/ITD mutation . This would include the prevalence, clinical implications, and disease mechanism of the mutation. Activation of FLT3 activates a signal transduction pathway that in turn, activates other growth pathways. Therefore, mutating this receptor can have a large impact on many different pathways. Current literature is focusing on what pathways FLT3/ITD is turning on/off and how new drugs can be used to target cancer cells expressing this mutation.

The last category is treatment for AML patients with FLT3/ITD. This is definitely a hot topic in the current literature due to the increase in targeted therapies, such as tyrosine kinase inhibitors, that are being used in combination with standard chemotherapy. The literature bounces back and forth between which treatments are most effective for this subset of cancer. There are also papers that are suggesting that using FLT3/ITD inhibitors causes further mutations and resistance to the FLT3/ITD inhibitors5. Unfortunately, there is no simple answer of which treatment is the most effective and as of right now, no literature source points to a single cure for AML.

 

References

  1. Rosnet, O, S Marchetto, O deLapeyriere, and D Birnbaum. 1991. “Murine Flt3, a Gene Encoding a Novel Tyrosine Kinase Receptor of the PDGFR/CSF1R Family.” Oncogene 6 (9): 1641–50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1656368.
  2. Nakao, M, S Yokota, T Iwai, H Kaneko, S Horiike, K Kashima, Y Sonoda, T Fujimoto, and S Misawa. 1996. “Internal Tandem Duplication of the flt3 Gene Found in Acute Myeloid Leukemia.” Leukemia 10: 1911–18. https://www.ncbi.nlm.nih.gov/pubmed/8946930
  3. Kottaridis, Panagiotis D, Rosemary E Gale, Marion E Frew, Georgina Harrison, Stephen E Langabeer, Andrea A Belton, Helen Walker, et al. 2001. “The Presence of a FLT3 Internal Tandem Duplication in Patients with Acute Myeloid Leukemia (AML) Adds Important Prognostic Information to Cytogenetic Patients from the United Kingdom Medical Research Council AML 10 and 12 .pdf.” Blood 98 (6): 1752–60. doi:10.1182/blood.V98.6.1752
  4. Jacobsen SEW, Okkenhaug C, Myklebust J, Veiby OP, Lyman SD. 1995. “The FLT3 ligand potently and directly stimulates the growth and expansion of primitive murine bone marrow progenitor cells in vitro: synergistic interactions with interleukin (IL) 11, IL-12, and other hematopoietic growth factors”. J Exp Med 1995;181:1357. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2191974/
  5. Alvarado, Yesid, Hagop M. Kantarjian, Rajyalakshmi Luthra, Farhad Ravandi, Gautam Borthakur, Guillermo Garcia-Manero, Marina Konopleva, Zeev Estrov, Michael Andreeff, and Jorge E. Cortes. 2014. “Treatment with FLT3 Inhibitor in Patients with FLT3-Mutated Acute Myeloid Leukemia Is Associated with Development of Secondary FLT3-Tyrosine Kinase Domain Mutations.” Cancer 120 (14): 2142–49. doi:10.1002/cncr.28705

 

 

 

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