CML cell growth is a population dynamics problem (which can be mathematically modeled). In a healthy / normally functioning immune system, CML cells are likely formed spontaneously in small numbers. Population is very small and proteins they secrete trying to tell the body's immune system - "hey - i'm part of you - don't attack" are too little to be effective.. A normal immune system recognizes the bad cell and either kills it directly (T-cell attack) or circulating proteins enter the cell and cause it to self-destruct (apoptosis).
When CML cells grow in population, however, they emit a sufficient amount of protective protein that causes T-reg cells to protect them from the immune system. This is how CML expands (and most cancers as well). It creates a cocoon of T-regs which run interference against T-NK cells.
Under normal conditions, CML population is controlled by the immune system and normal people would never even know they have bcr-abl circulating around. It gets created and then destroyed.
We, who developed CML disease, did so either because a sudden spontaneous large population of bcr-abl cells were created all at once (radiation can do this - that is what I believe happened to me) or it's possible, the immune system weakened enough so that the few CML cells that were created were able to expand and the population was too great to be controlled on its own.Either way, the population of CML stem cells became great enough in number to be self-sufficient and evade immune surveillance.
Enter TKI's.
TKI's are like a flea bomb. They augment the body's CML cell population control precisely by entering the CML cell, attaching to the ATP energy site which causes the CML cell to self-destruct during division.
By having enough TKI present to cause the population of CML cells to trend down, a new population equilibrium is established. If the new equilibrium is around PCR ~ 0.1%, data suggests, CML does not progress. Keep in mind, CML cells are always dividing; in the presence of TKI, some, not all LSC's, get killed. As long as we take our TKI, the population of CML cells is greatly controlled at a very low residual level. The reason it is not zero is because Leukemic CML stem cells re-populate the killed daughter cells. TKI's do not affect dormant LSC's.
Regarding mutations.
TKI's are designed for a specific gene arrangement of CML which kills that cell type only. Those cells on their own do not mutate. They are already differentiated. It is the stem cells and daughter stem cells which can mutate. Either a pre-existing population of mutated stem cells already exists or a new population of mutated cells gets started. The fact that LSC's can stay dormant for years is a likely source of mutation. Fortunately this is rare.
The reason the 'odds' of CML mutation and subsequent relapse is unlikley when CCyR levels drop to zero (i.e. FISH = zero; PCR ~ 1.0%), is because LSC population is also reduced. Keep in mind, every time an LSC divides, it is killed in the presence of TKI. So by the time FISH = zero occurs, the originating LSC population is also greatly reduced - just not eliminated. And that becomes the steady state most people achieve. A balance between LSC's that are dormant coming out of dormancy and creating replacement CML cells which are then killed by TKI. Each of us has a different population equilibrium - many will achieve MMR, some will only achieve a stable PCR ~ 0.1%. And that is sufficient to keep CML in check.
Over time - for 45% of two years of PCRU - enough LSC's are killed off that treatment free remission is possible. This doesn't mean that all LSC's are gone - just that the population is so low that the persons immune system can keep it in check.
