Most cells in the human body each contain about six feet of DNA. Yet the nucleus, where DNA is coiled, is no larger than a single speck of dust. Despite its density, DNA is not a tangled ball of yarn. It is organized into intricate layers of loops that fold and unfold in response to cues from the cell.

Scientists know that the three-dimensional shape of DNA is important. This long helical thread is peppered with genes that are translated into proteins to drive cellular activity. And the structure of the genome —those layers of loops—determines which genes are active at any given time.

How the three-dimensional structure of the genome is maintained, however, is less clear. Structural changes and abnormalities are associated with many diseases, such as cancer and developmental disorders. Identifying what controls genome structure could yield targets for treatment.

Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C to be a key factor for B-cell ALL (B-ALL) development and maintenance. While cyclin C is not essential for normal hematopoiesis, CcncΔ/Δ BCR::ABL1 + B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in CcncΔ/Δ BCR::ABL1 + cells resulting in the inability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as a potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy.

The Philadelphia (Ph) chromosome, a product of the reciprocal translocation t(9;22)(q34;q11) between chromosomes 9 and 22, encodes the BCR::ABL1 fusion oncoprotein.¹ The constitutively active BCR::ABL1 tyrosine kinase is a hallmark of chronic myeloid leukemia (CML) and drives a subset of acute lymphoblastic leukemia (ALL). The incidence of Ph positive (Ph⁺) ALL correlates with age, from only 3% in pediatric ALL to around 25% in older adults.² Direct targeting of the BCR::ABL1 kinase with tyrosine kinase inhibitors (TKI) has been a breakthrough in targeted cancer therapy. Despite efforts to counteract TKI resistance and improve safety profiles, refractory BCR::ABL1⁺ leukemia, as well as toxicities and long-term side effects of TKI, present particular therapeutic challenges.^3–5

The clinical relevance of cyclins and their associated cyclin-dependent kinases (CDK) has been a major focus of research for several years. Cyclin-CDK complexes do not only drive the cell cycle, but are also important players in various other cellular processes including transcriptional and epigenetic regulation, metabolism or stem cell self-renewal.⁶ In line with their importance in different pathways, cyclin-CDK complex dysregulation is implicated in many different types of cancer.⁷

A new study has unveiled when chronic myeloid leukaemia, a type of cancer that affects the blood and bone marrow, arises in life and how fast it grows. Researchers reveal explosive growth rates of cancerous cells years before diagnosis and variation in these rates of growth between patients. Such rapid growth rates had previously not been observed in most other cancers.

Researchers used whole genome sequencing to study when BCR::ABL1 – an abnormal fusion of the different genes called BCR and ABL1, which is known to cause chronic myeloid leukaemia. The team investigated when BCR::ABL1 first arises in a blood cell and how quickly these cells with this genetic change then multiply and expand to lead to a diagnosis of a type of leukaemia.

The research, published in Nature, contributes to the scientific understanding of how strong this abnormal fusion gene is in its ability to drive cancer.