What is clonal evolution?

What is clonal evolution? So we're learning now about another entity, I won't call it a disease, an entity called clonal hematopoiesis. As we age, the bone marrow is responsible for a lifetime of making blood cells, and sometimes mistakes happen. Sometimes those mistakes aren't well tolerated and that stem cell just dies. Sometimes those mistakes persist and don't really change the function of that stem cell, and sometimes those mistakes happen and give that stem cell a very slight growth advantage. That slight growth advantage can persist for decades and never cause the patient any problem whatsoever. So we have a vast, vast, 96 plus percent of patients who have clonal hematopoiesis, never have any alterations in their blood counts, never have any abnormal leukemia or pre-leukemia like condition. Now some of those patients will go on to have a pre-leukemia like condition we call myelodysplastic syndrome. Myelodysplastic syndrome is essentially a bone stem cell population that doesn't work very well. It's inefficient. It's not responding to that same signal of, hey, we need more red blood cells. Hey, we need more white blood cells, the way a normal bone marrow stem cell would do. And so blood counts can be on the lower side, and sometimes they'll pick up additional cytogenetic abnormalities as the cause of this, or DNA mutations that'll be the cause of this. But these patients sometimes need therapy and sometimes don't need therapy. There's really a very broad spectrum of therapeutic interventions and strategies for myelodysplastic syndrome. But those bad stem cells, those bad myelodysplasia cells can evolve over time to get an additional mutation or an additional signal that is going to cause it to begin to proliferate and grow and outcompete the normal healthy bone marrow. And that's ultimately when these patients convert into acute myeloid leukemia. Now, not all acute myeloid leukemia needs to go through that clonal hematopoiesis to MDS to AML pattern. Sometimes a stem cell just is really unlucky and picks up a mutation that is enough that that one cell starts to grow, and that's the leukemia from the beginning. And sometimes even in those cases, those leukemias will pick up additional mutations over time. And so we've learned now from some single cell DNA sequencing that leukemias are really heterogeneous. So sometimes leukemias have lots of different small populations, much like the branches on a tree. And so they may share the same trunk, but they've now diverged slightly different from one another to really represent a population of slightly different cells that have the same origin. And so in this, we call this clonal evolution, this separation of different types of clones, different cell populations with a given mutational profile. Essentially we have to think about what are the best ways to get rid of the leukemia. And sometimes it actually means cutting off large branches. I think we would hope that we would have the tools to really cut the tree out by the roots. Now we're very much at the beginning of trying to understand what are the inciting events, what are the dependent events that would permit the entire leukemia tree to fall over. But it does mean that the mutational profile has to be interpreted in the context of what else is going on in the bone marrow.