20.109 TR Yellow Mod3 Research Proposal

Determining the oncogenic effect of supposedly non-oncogenic genes associated with AML

A recent study published in nature [1], where the full genome of a cancerous growth was sequenced and compared to healthy tissue. 10 mutations were identified, 2 of which were well-known AML-associated mutations, 4 of which were mutations in genes belonging to cancer-associated families, and 4 of which were mutations to genes not previously associated with cancer but rather with metabolism.

Some of the discussion of the article centers around the uncertainty of whether the 8 non-AML mutations are "driver" or "passenger" mutations, i.e. whether they were crucial to the growth of the cancer, or just happened at the same time as the cancerous mutations.

What we are proposing is doing a panel of knockout studies with the 4 metabolism-associated genes (KNDC1, GPR123, EBI2 and GRINL1B) identified in the previous study, both with and without the AML-associated mutations in NPM1 and FLT3. This is to see both whether any of the metabolism-associated genes are "driver" genes on their own or in combination with any of the other metabolism-associated genes, as well as to see whether any combination of the metabolism-associated genes is required for mutations in NPM1 and FLT3 to cause cancer.

Related Articles

http://www.ncbi.nlm.nih.gov/pubmed/18507500?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4&log$=relatedarticles&logdbfrom=pubmed "Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis"

This paper talks about how the identification and study of mutation has led to better treatment

Similar in that they used a complete genome approach and found many key genes.

http://www.ncbi.nlm.nih.gov/pubmed/10098750?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedarticles&logdbfrom=pubmed "Mechanisms of relapse in acute leukaemia: involvement of p53 mutated subclones in disease progression in acute lymphoblastic leukaemia"

p53 mutations are very common in leukaemia. This paper probably won't be that helpful, but would be a type of mutation to look for in our assay.

http://www.ncbi.nlm.nih.gov/pubmed/17194187?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedarticles&logdbfrom=pubmed "A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies"

Methylation and loss of heterozygosity causes loss of gene function in tumor cells.

Although the work is done using lung cancer mutations, the researchers believe that methylation of a gene could be used to detect cancer earlier

Probably not that helpful

http://www.ncbi.nlm.nih.gov/pubmed/18446232?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed “Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling.”

Isolated methylated genes in cancer cells: biomarkers for cancer identified.

In our context: newly identified genes might not only be useful for treatment approach, but for earlier identification of the cancer.

http://www.ncbi.nlm.nih.gov/pubmed/10071127?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed “Alterations of the p53, p21, p16, p15 and RAS genes in childhood T-cell acute lymphoblastic leukemia.”

Sequenced genes and looked for mutations. This represents the kind of work we could do to determine how common/significant the newly identified mutations are in leukemia.

http://www.ncbi.nlm.nih.gov/pubmed/7727782?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedarticles&logdbfrom=pubmed “Mutations of the p53 and ras genes in childhood t(1;19)-acute lymphoblastic leukemia”

This paper is very similar to the above paper, except that it just examines p53 and ras genes. Seems to be the precursor to that paper.

http://www.ncbi.nlm.nih.gov/pubmed/9379679?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedarticles&logdbfrom=pubmed “Exon 5 mutations in the p53 gene in relapsed childhood acute lymphoblastic leukemia”

An analysis of a very specific mutation (p53 exon 5) that seem to be common in this form of leukemia. This work is the kind of thing we could do to further characterize the importance of a mutation if one of the newly identified mutations seems to be common in leukemia.

http://www.ncbi.nlm.nih.gov/pubmed/9279367?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedreviews&logdbfrom=pubmed “The non-random distribution of point mutations in leukemia and myelodysplasia—a possible pointer to their aetiology”

In this paper they searched of all the known mutations (at the time—1997 so a while ago) and what caused the mutation (base pair changes etc)