In 1993 Metcalf proposed the hypothesis many factors are needed for regulation of the hematopoietic stem cell (HSC) compartment. In other words – can deletion of a single HSC gene-regulator be sufficient to cause any abnormal phenotype or cancer, or should multiple gene mutations occur?
From many scientific reports we know that deletion of just one gene could lead to HSC cell-cycle dysregulation and expansion. But what will happen if we delete just one gene from a whole gene family? Because scientists like to make a simple picture more complicated they decided to check it and created so-called TKO = triple knockout mice.
2 excellent reports, based on TKO study, came up this year and showed that everything is much more complex then we knew before.
The first study from Michael Clarke group at Stanford U demonstrates that deletion of one gene causes HSC expansion as much as twice, but if 3 genes (downstream of Bmi-1) are deleted at the same time – a robust 10-fold increased function of HSCs occurs.
The authors made a conclusion that multiple genetic mechanisms regulate the frequency of HSC self-renewal. If these 3 regulators of HSC self-renewal are epigenetically repressed by Bmi-1, then in malignancy we see their mutations (deficiency). This difference could hint to potential cancer therapeutic targets.
Another, recently published paper, shows that deletion of 3 genes – members of retinoblastoma (Rb) tumor gene supressor family, leads to cell cycle dysregulation, HSC expansion and finally, development of hematological malignancies in mice. Interestingly, deletion of all of 3 genes together leads to myelo-proliferative disease development.
Picture shows what Rb family TKO (genetic ablation of Rb, p107, and p130) makes with a hematopoietic cells (credit: Patrick Viatour, 2008):
If we look at back to 2006 when Orkin’s group described phenotype of Rb-knockout mice, we can see that a single gene deletion has no effect on HSC function.
… primitive hematopoietic cells presumably use many different molecules in the same pathway to regulate their normal function. It is only when all members of the pathway were disrupted that severe effects in HSC physiology were observed.
So, on one hand, downregulation of those genes promotes stem cells to exit from a quiescent state and enter into cell cycle, leading to their expansion, exhaustion and cancer development, but on the another hand, the involvement of multiple genes could protect them from it. They always have a time between a first hit mutation and a number of mutations enough for cancer initiation and manifestation. It can also explain why we can carry just one mutation in hematopoietic cells without leukemia development.