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Chronic Myelogenous Leukemia is a form of cancer that starts in the blood-forming cells of the bone marrow, or hematological stem cells, and invades the blood. The disease was first recognize in 1845 when it was shown that CML was a blood cell disease characterized by excessive white blood cell accumulation. However, a molecular understanding of the cause of CML was not determined until 1960. Using high-resolution karyotyping/ chromosome banding, it was determined that the disease was caused by a reciprocal translocation between the tips of the long arms of chromosome 9 and 22. It is later determined that this reciprocal translocation event led to the fusion of the c-ABL gene and the BCR gene, creating a chimeric BCR-ABL protein product.

            The structural understanding of BCR-ABL eventually led to the development of imatinib, a CML therapy that works as a potent and selective Abl inhibitor. Although initially skeptical of a any tyrosine kinase inhibitors, imatinib was shown to be a valid and potent treatment for CML. However, challenges remain as imatinib resistance has been shown to occur especially in blast crisis patients who have shown to evolve mutations in BCR-ABL, specifically the Thr315Ile mutation that blocks imatinib activity. Further research into more long-term therapies as well as second generation drugs to combat mutations can lead to longer and lasting remission in CML patients.  

This included knowledge of the N-Terminal BCR sequences being joined upstream of the c-ABL SH3 and SH2 domains as well as several functional motifs including actin binding, as well as nuclear imort and export sequences. Further analysis indicated that BCR, through the use of its coiled-coil domain allowed the BCR-ABL protein to oligomerize. Conserved C-terminal F-actin binding domain in the BCR-ABL fusion protein localizes it in the cytoplasm as opposed to normal c-Abl activity which involves shuttling between the nucleus and cytoplasm to effect DNA damage pathways. The BCR-ABL fusion protein also was determined to obtain unregulated tyrosine kinase activity due to the autophosphorylation at Tyr 1127 in the SH2 catalytic domain linker which disrupts its binding to the SH3 domain.

In order to better understand the mechanism of the chimeric BCR-ABL protein, scientists used other oncoproteins and tumor viruses. For example, the first work involving oncogenic protein kinases revolved around the Rous sarcoma virus oncogene product (v-Src). The Src protein was shown to have highly similar negative regulatory mechanisms to that of Abl. This includes the SH2 and SH3 domains which inhibit kinase activity in both proteins. Both proteins use myristates as well as intramolecular interactions between the SH3, SH2 and kinase domain to inactivate kinase activity. By 1990, sequencing of the BCR-ABL protein allowed scientistsp to categorize the domain structure of c-ABL as well as the BCR-ABL product.

Chronic Myelogenous Leukemia is a form of cancer that starts in the blood-forming cells of the bone marrow, or hematological stem cells, and invades the blood. The disease was first recognized in 1845 when it was shown that CML was a blood cell disease characterized by excessive white blood cell accumulation. However, a molecular understanding of the cause of CML was not determined until 1960. Using high-resolution karyotyping and chromosome banding, it was determined that the disease was caused by a reciprocal translocation between the tips of the long arms of chromosome 9 and 22. It was later determined that this reciprocal translocation event led to the fusion of the c-ABL gene and the BCR gene, creating a chimeric BCR-ABL protein product.

Research and drug development regarding CAR T-cell therapies has been rapidly progressing and expanding over the past few years. In order to attack the ‘antigen loss’ problem, researchers are looking into potential other antigen targets that can be used in combination with CD19 CAR T-cells as a form of treatment ‘cocktail’. Researchers have also been looking into application of CAR T-cell therapy  for patients with blood cancers and solid tumors.  Therapies regarding solid tumors have proven difficult due to the microenvironment of the tumor that makes immune response extremely difficult.

CAR T-cell therapy and immunotherapy in general has shown great promise. Continued funding and research can lead to fine-tuning of drug therapies as well as targets for different kinds of cancers. Immunotherapy at this point should not be looked at as a ‘silver bullet’ to cure cancer, however it can be another tool that oncologists can use to improve standard of living and remission length.

Traditional treatment of cancer has always been based on invasive surgery, chemotherapy and radiation. However, with advances and molecular biology and biochemical engineering, immunotherapies, or therapies that use the patients own immune system to attack tumors has been gaining traction and shown a lot of promise. This generally works by the extracting a patients T cells through a process called leukapheresis and then genetically modifying those T cells to express a chimeric antigen receptor through the use of retrovirals and then injecting the modified T cells back into the body to bind tumor antigens. The modified T-cells are only injected into the patients body after their immune system is completely depleted. The most common antigen target of drugs furthest along in development is an antigen found on B cells called CD19.

I took Resource Economics Statistics 212 in the Spring of 2016 with Professor Wayne. The class was structured as a TBL and most of the work was done in groups. The class taught basic statistical principles as well as how to use Microsoft excel to apply those principles and was focused in social science and business-related fields. The key concepts taught were probability theory, hypothesis testing and normal distribution analysis. This including chi square analysis and when to accept or reject a null hypothesis as well as t and z tables. I was able to apply some of those concepts in my Genetics class this past fall. The excel portion of the course was useful in actually constructing relevant tables and figures using large amounts of data. Overall, what I took away from the course was that statistics can often be misleading when not analyzed and applied properly. 

G-protein-coupled receptors, or GPCRs, are the common mode of receptor singling via GTP binding proteins and thus play a key role in the mediation of a wide variety of different physiological signals. The polypeptide chain that makes up GPCRs passes through the plasma membrane of the cell seven times and can also be called 7-tm receptors. Due to their importance in the signaling of changes in the concentration of hormones, lipids, neurotransmitters, photons and more, determining the mechanism for G-protein-coupled receptors and how it is able to discriminate and regulate these signals were questions of paramount importance to medicine and molecular biology.