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, Ccnc\u0394\/\u0394 BCR::ABL1 <\/i>+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in Ccnc\u0394\/\u0394 BCR::ABL1 <\/i>+ 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.<\/p>\n
The Philadelphia (Ph) chromosome, a product of the reciprocal translocation t(9;22)(q34;q11) between chromosomes 9 and 22, encodes the BCR::ABL1<\/i> fusion oncoprotein.1<\/a><\/sup> The constitutively active BCR::ABL1<\/i> 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+<\/sup>) ALL correlates with age, from only 3% in pediatric ALL to around 25% in older adults.2<\/a><\/sup> Direct targeting of the BCR::ABL1<\/i> 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<\/i>+<\/sup> leukemia, as well as toxicities and long-term side effects of TKI, present particular therapeutic challenges.3\u20135<\/a><\/sup><\/p>\n 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<\/a><\/sup> In line with their importance in different pathways, cyclin-CDK complex dysregulation is implicated in many different types of cancer.7<\/a><\/sup><\/p>\n","protected":false},"excerpt":{"rendered":" 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 [\u2026]<\/p>\n","protected":false},"author":662,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11,412],"tags":[],"class_list":["post-211898","post","type-post","status-publish","format-standard","hentry","category-biotech-medical","category-genetics"],"_links":{"self":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/211898","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/users\/662"}],"replies":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/comments?post=211898"}],"version-history":[{"count":0,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/211898\/revisions"}],"wp:attachment":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/media?parent=211898"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/categories?post=211898"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/tags?post=211898"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}