In this issue of Blood, Imgruet and colleagues investigate how loss of the tumor suppressor gene Cux1 modulates DNA repair activity in the hematopoietic compartment and how this contributes to the pathogenesis of therapy-related myeloid neoplasms (tMNs).1
The blood system has tremendous regenerative capacity, which is called upon in response to blood loss, severe infections, and exposure to toxins, including systemic chemotherapy. Frequently, the blood system will reemerge from the ashes, but unlike the mythical phoenix, which rises reborn, the blood system comes back altered, and the fire will sometimes rage out of control. One way that this manifests is in higher rates of clonal hematopoiesis, myelodysplasia, and acute leukemia in the years following cancer treatment. This is a significant problem, because hematological malignancies that arise after therapy are difficult to treat and generally have poor outcomes.
CUX1 is a multifunctional protein, implicated in gene regulation, cell-cycle control, cell signaling, apoptosis, and the DNA damage response, and its role in cancer is predictably complex.2 CUX1 is typically impaired in myeloid neoplasms; it is lost in around half of all cases of tMN, mostly through loss of chromosome 7, but sometimes through focal deletions or other mutations.3 Mice engineered to have low Cux1 expression are predisposed to myelodysplasia.4 In line with earlier work in cell lines, the investigators show loss of Cux1 impairs the DNA damage response in primary murine hematopoietic stem and progenitor cells. Cux1-deficient progenitors expand after treatment with the alkylating agent N-ethyl-N-nitrosourea, and the stress encourages the rapid outgrowth of erythroleukemia, providing a new way to model this aggressive disease.
The investigators employ various functional assays to assess DNA repair activity in Cux1-deficient cells. They probe the response to DNA damaging agents, stain for DNA damage markers, and survey DNA strand breaks with COMET assays. None of these assays is perfect, but together they build a case that implicates Cux1 in modulating the DNA damage response. How does this occur? Again, it seems CUX1 acts at multiple levels. Imgruet et al suggest Cux1 recruits histone-modifying complexes to sites of damage and that this helps nucleate DNA repair. Some suggest a broader role, coordinating the expression of multiple DNA repair components, particularly in the ATM/ATR pathway.5 Others suggest CUX1 directly modulates the activity of glycosylases, like OGG1, that repair oxidative damage.6 More work is required to determine which of these activities is most crucial, or whether they work in concert.
The question then becomes, are CUX1-deficient cells accumulating more DNA damage? It is possible, but the answer is not yet definitive. By pulling together exome data from patients with various myeloid neoplasms, it appears CUX1-mutated samples have a slightly higher total mutation burden.1,7 However, the difference is modest, and these comparisons are complicated by the low number of cases, the diverse disease spectrum, and differences in age, treatment history, and lifestyle factors. One way to answer this question would be to perform whole-genome sequencing on clonal cultures of blood cells to reveal the mutation burden associated with CUX1 deficiency, either in the mouse model or in material from patients.8 Studying the resulting mutational signatures, during steady state and in response to stress, will help reveal any underlying DNA repair defect.
If there is more DNA damage, are these mutations driving disease progression and poor outcome? The prevailing view is that DNA damage provides more fuel for the fire. Here, the authors reveal the power of their mouse model, which allows them to transiently lower Cux1 expression.4 They show that reintroducing Cux1 rescues erythroid differentiation and prevents myeloid transformation, suggesting that any DNA damage that has accumulated is not enough to drive disease progression. This is exciting, because it suggests that drugs that restore CUX1 function, or that act downstream of this multifunctional regulator, may offer a way to treat the disease. Indeed, targeting altered signaling and survival pathways in CUX1-deficient cells seems to be a promising strategy.9 Although encouraging, it will be important to pursue these questions in more relevant clinical models that mirror the complexity of the disease.
We are just beginning to appreciate the influence of cancer therapies on the blood system.10 This understanding will grow as we learn to model treatment response, and as we apply new technology, like cellular barcoding, single-cell transcriptomics, and mutational profiling. Together, these approaches will help to reveal how complex, multifunctional tumor suppressors, like CUX1, safeguard the blood system. Cytotoxic chemotherapy remains a mainstay of cancer therapy, indicating that we will be dealing with this problem for some time to come. By modeling treatment response, I am hopeful that we can learn to rekindle the hematopoietic system safely and avoid starting a raging inferno.
Conflict-of-interest disclosure: The author declares no competing financial interests.