A New Drug Inhibits the Alternative Splicing of Self-Renewal and Survival Genes that Protects Leukemia Stem Cells from Chemotherapy

Drug resistant leukemia stem cells (LSCs) that are sequestered in the bone marrow can be sensitized to the action of tyrosine kinase inhibitors (TKIs) such as imatinib, gifitinib, and sunitinib by treatment with the investigatory drug sabutoclax.

Investigators at the University of California, San Diego School of Medicine (USA) and other institutions including the Sanford-Burnham Medical Research Institute (La Jolla, CA, USA) have found that alternative splicing of BCL-2 genes in LSCs favored the expression of prosurvival proteins that protected the insipient cancer cells from drug treatments.

Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing. The resulting different mRNAs may be translated into different protein isoforms, thereby allowing a single gene to code for multiple proteins. Alternative splicing occurs as a normal phenomenon in eukaryotes, where it greatly increases the biodiversity of proteins that can be encoded by the genome. In humans, about 95% of multiexonic genes are alternatively spliced. Numerous modes of alternative splicing have been observed, of which the most common is exon skipping. In this mode, a particular exon may be included in mRNAs under some conditions or in particular tissues, and omitted from the mRNA in others. Abnormal variations in splicing have also been implicated in disease, since a large proportion of human genetic disorders result from splicing variants. Abnormal splicing variants are also thought to contribute to the development of cancer.

Results appearing in the January 17, 2013, online issue of the journal Cell Stem Cell revealed that sabutoclax, a pan-BCL-2 inhibitor rendered LSCs sequestered in the bone marrow sensitive to TKIs at doses that spared normal progenitors. Furthermore, sabutoclax destroyed cells by suppressing some members of the Bcl-2 protein family. Bcl-2 proteins are involved in apoptosis, the normal cellular process of programmed cell death. Sabutoclax blocked anti-apoptotic Bcl-2 proteins that would otherwise have kept the cancer cells from dying.

“Our findings show that pan-BCL-2 inhibition will be critical for the eradication of cancer stem cells in chronic myeloid leukemia and that there is an essential link between cancer stem cell dormancy, pro-survival BCL-2 isoform expression, and therapeutic resistance,” said senior author Dr. Catriona H. M. Jamieson, associate professor of medicine at the University of California, San Diego. “By using a novel pan-BCL-2 inhibitor, we may be able to prevent therapeutic resistance by sensitizing malignant stem cell clones to TKIs.”

Related Links:
University of California, San Diego School of Medicine
Sanford-Burnham Medical Research Institute