How Proteins in Leukemia Cells are Modified to Function differently Than in Normal Cells
The complex, yet efficient biochemical processes that define living organisms fascinate me.
A rewarding childhood experience for me and my siblings was trying to describe the biological chemistry behind traditional practices to our elderly grandparents. Explaining these connections brought us a great sense of accomplishment, as was watching our elderly grandparents reactions tether between curiosity and unbelief. A few experiences stand out – ancient techniques for processing cassava plant, a staple food in Nigeria, efficiently removes up to 95% of lethal cyanide. The plausible scientific explanation – these techniques provided the appropriate cellular environment for the plant protein linamarase to hydrolyze cyanide containing substrates. The complex, yet efficient biochemical processes that define living things fascinate me. Towards the end of my graduate degree in biochemistry, I was determined to further explore how knowledge of biochemical processes can be harnessed to understand and better tackle human diseases, specifically, cancers. In Dr. Philipp Lange’s research team, my research is focused on studying how proteins in leukemia cells are modified to function differently than in normal cells.
In the human body, instructions on what proteins make and when to make them are uniquely controlled by each individual’s genes. Proteins oversee the general wellbeing of cells, the building blocks of all living beings. Their importance can be likened to the roles of both umpires and referees in a game of cricket –in this case a game of cell survival, growth and defense. Proteins detect signals from within and outside the cell environment, process these signals, and take consequent actions that either preserve or destroy the cells – yes, sometimes it is a good decision to destroy a cell, especially when it shows signs of transformation into a ‘cancer cell’ .
To further diversify their functions, proteins are often ‘modified’ in cells. For example, some proteins are activated only when small chemical groups are added to them. The addition of such chemical groups could be in response to changes within the cell or could be a direct consequence of signals from outside the cell’s environment.
Pediatric acute lymphoblastic leukemia (ALL) is a childhood cancer that affects blood cells. Here, a child could have inherited defects in genes, or could have developed some defects in genes, and hence proteins, which adversely compromise the integrity and function of blood cells. These defects or mutations specifically make the affected blood cells to rapidly grow and divide. The uncontrolled increase of these ‘unwanted’ cells leads to severe problems in the body. It is interesting to note that some of these cells have specific proteins on their surface or in the cells, that can be used to target or detect them. Knowing these proteins has for sure made it possible to detect these cells, and more importantly to design drugs that could specifically target these cells for destruction.
Although most therapies targeting cancer work by acting on proteins, the scenario is not as rosy as it seems because cancer cells do not want to be targeted for destruction. These cells therefore continuously evolve their ‘protein make-up’ or ‘proteome’ to evade normal or drug-induced destruction. Such evasive capabilities explain the difficulties in treating some types of pediatric leukemia, as well as the almost fatal consequence of recurrence of the disease. How about if researchers can consistently and accurately study the proteome of cancer cells? This would mean accurately examining “all’’ proteins and protein modification changes that occur in cancer cells at any given condition or location in the human body. How would such knowledge support existing approaches for diagnosing, treating, and monitoring patients?
Comprehensively mapping differently modified proteins and their functions could help uncover targets for more precise therapies that attack cancer cells without affecting healthy cells. A decade ago, this would have been like searching for a needle in a haystack. However, in Dr. Lange’s research laboratory, I use techniques that enable the large-scale study of proteins and protein modifications (the proteome) in cells, tissues and organs. These ‘proteomic’ techniques use specialized instruments called mass spectrometers, and support fast and comprehensive study of the proteome of many samples in a short time.
In my recent study on a type of pediatric ALL, I utilized proteomic techniques to quantify over 6000 proteins in bone marrow samples of children with recently diagnosed or recurrent B-cell and T-cell acute lymphoblastic leukemia. These results showed clear differences in protein composition in leukemic bone marrow when compared to bone marrow of healthy children. I also studied specific types of protein modifications in childhood ALL.
First, the addition of one or more phosphate groups to a protein – a modification that is well-known to activate or deactivate proteins associated with pediatric B- and T- ALL.
Second, a less studied modification type, ‘limited proteolyis’, which occurs when a protein is irreversibly cut into shorter fragments that could have functions different from the parent protein. I wanted to know if evidence of such ‘new’ protein forms could be uniquely detected in leukemic cells, and if functional roles exist for these modified proteins. Using proteomic techniques developed in Dr. Lange’s laboratory, numerous phosphorylation (>3,500) and proteolytic (>3,000) modifications were detected in bone marrow / plasma samples collected from 12 leukemic patients at diagnosis or relapse stage of the disease. My present research focus is on understanding the function of selected protein modification events that were detected in leukemic samples, by simulating these modifications in pediatric ALL cell lines, and evaluating the effect of these modifications on cancer cell growth, survival and response to drugs.
In summary, I hope that if we can map protein and protein translational modification on a global scale for many childhood diseases, it can improve our chances of better targeting diseases in terms of developing drugs and therapies with less side effects on healthy cells.