I read and reread (and rereread…) this full study (grazie, Sherlock!) that I reported about in my January 19 post. Definitely one of the the most difficult texts I have ever read, and I have read some labyrinthine stuff, believe me! Anyway, a few things are clear (more or less…?), so I thought I would post about them today, hoping not to make any huge mistakes…
An important finding is that the pre-leukaemic stem cell population derived from the abnormal merging or, to use a more appropriate technical term, the “chromosomal translocation,” of two genes during pregnancy. From their union sprang a fusion gene called “TEL-AML1,” a clone that forms in one twin inside the womb that “may spread to the other twin via their shared placenta.” It’s a genetic “mistake” that can lead to the development of leukaemia. Or not, as in the case of these British twins.
In fact, the study tells us that “Additional mutations are required for progression to leukaemia,” which means that one twin may develop leukaemia while the other remains healthy, in spite of carrying the “ancestral preleukemic clone.” The researchers found that Isabella (the healthy twin)’s peripheral blood contained a “rare population” of these mononuclear cells, which has remained stable. This would prove that one mutation alone does not trigger full-blown leukaemia.
The “cancer-propagating population," or "rogue stem cell population," (which I like better) was present in both twins, but there were differences between the two. In the leukaemic twin, there was “a clonal and more differentiated descendant of the CD34+CD38–/lowCD19+ population in the healthy twin. Consistent with this, the majority of CD34+CD38–/lowCD19+ cells in the leukemic twin express common ALL antigen, CD10; those in the healthy twin do not.”
I know, I know…but this long string of letters and numbers, CD34+CD38–/lowCD19+, simply indicates the cancerous stem cell population. So the healthy twin’s cells present less differentiation, in sum. And her blood does not carry the acute lymphoblastic leukaemia (ALL) antigen, called CD10. Am I the only one who finds this fascinating? If not, and if you are getting a headache, just skip to the bottom of my post, where I wrote a summary of sorts.
The researchers then injected these pre-leukaemic cells into NOD/SCID mice. NOD (I looked it up out of curiosity) are “non-obese diabetic” mice. SCID are “severe combined immunodeficient” mice. SCID mice are frequently used in research dealing with the immune system in part because they lack the capacity to make T or B lymphocytes (so they cannot fight infections). I must say, I have a hard time reading all these details. When I was a kid, I would burst into tears whenever I heard about suffering, hurt or dead animals of any size. In many ways, I am still that kid. I haven’t been able to watch the "March of the Penguins," for instance. Or that wonderful movie about migrating birds…(when the hunters began shooting at those beautiful birds…well, you can imagine the rest!) Or even…"Bambi." I may be the only adult in the western world who hasn’t seen Bambi. But that is neither here nor there. It’s just that these feelings of empathy curtail my current plans to become a molecular scientist in my next life. I think I’d gather up all the mice in the lab and take them home…
But let’s get back to the study. What the team of researchers found was this: “Collectively, our data support the notion that TEL-AML1 can, as a single mutation, generate abnormal cells that resemble the TEL-AML1– expressing CD34+CD38–/lowCD19+ cells observed in the healthy twin.” If I understood this correctly, this means that the researchers were able to reproduce the pre-leukaemic population in the NOD/SCID mice. The transplanted cells resembled those found in the healthy twin’s blood and “displayed B cell differentiation and self-renewal potential in vitro.” They also did not contain the CD10 antigen, like the healthy twin’s peripheral blood cells.
The team then transplanted the rogue stem cells from the “primary” (first bunch of) mice into a bunch of “secondary” NOD/SCID mice: "To investigate whether the TEL-AML1–generated CD34+CD38–/lowCD19+ population can initiate and maintain a ‘preleukemic’ state in vivo, we prospectively isolated these cells from engrafted primary mice and injected them into the tibiae of secondary NOD/SCID recipients.”
These cells not only engrafted but, to the team’s surprise, also “gave rise to more mature B cells (CD38+CD19+), as well as reconstituting a CD34+CD38–/lowCD19+ population.” This means that the stem cell population, or “TEL-AML1–generated CD34+CD38–/lowCD19+ population has significant self-renewal potential.” What does all this mean? It indicates that this CD34+CD38–/lowCD19+ cell is able to reproduce itself, and it “may itself function as a preleukemic stem cell. This proposal is supported by our xenograft modeling studies, which further suggest that TEL-AML1 may be sufficient to generate this population of preleukemic stem cells.” Ok, TEM-AML1 is definitely the bad guy in this scenario.
The team also suggests that there is a hierarchical structure not just in full-blown leukaemia but also in pre-leukaemic cells. I am not sure why this finding is important, but apparently it is. If anybody knows the answer (I don’t have time to look into this matter now), please let me know.
Anyway, the study of the stem cell population, the researchers add, is crucial in order to understand “the function of the first-hit mutation and how it predisposes to leukaemic transformation.” Okay.
The study ends as follows: “The observation that children in lengthy remission can relapse late with a novel leukemic clone, but which nonetheless appears to derive from the identical preleukemic clone that initiated the disease at presentation, suggests that the preleukemic stem cell compartment may persist even when the cells propagating the overt leukemia have been effectively eradicated.” So the model created by these researchers may provide an explanation as to why pre-leukaemic stem cells can resist chemotherapy treatments. When that (resistance) happens, sooner or later the cancer will return.
There have been other studies on twins and ALL. I just wanted to highlight this one, published in "Leukemia" in 2003: http://tinyurl.com/ypom65 In this case, both twins (two years old) developed ALL. Here, too, the researchers suggested that these pre-leukaemic cells formed in the womb and spread from one twin to the other. And the researchers state that "It is likely that one or more additional postnatal genetic events was required for overt leukemogenesis." Aha, the "two mutations needed" theory that we discussed previously. Okay, that’s it for today. I still have my classes to prepare for tomorrow! Agh!
Summary of the 2008 study, as I understand it:
- Acute lymphoblastic leukaemia (ALL) is the most common form of childhood leukaemia.
- Researchers identified a “rare population” of CD34+CD38(-/low)CD19+ cells isolated from the TEM-AML1-positive twins.
- The leukaemia-causing potential of this small population was confirmed when the researchers were able to transplant the cells of the leukaemic twin into a group of NOD/SCID mice. Successfully. And a second transplantation, from the first to a second group of mice, was also successful. The rogue stem cells survived and proliferated in the second group, too.
- This indicates that these cells are self-renewing leukaemic stem cells.
- The healthy twin only had one genetic defect, whereas the leukaemic twin also carried a second genetic mutation (the loss of the "uninvolved" normal TEL allele or gene, for the science brains among us).
- The second mutation may have been triggered by an infection, which may have led to the development of leukaemia in one of the twins. No second mutation = no leukaemia, then, it would seem.