Prominin-1 (CD133) is essential for the determination of the phenotype of Philadelphia chromosome-positive leukemia.

Abstract

The human PROMININ-1 (PROM-1, CD133), detected by its AC133 epitope, is expressed on the surface of leukemia-initiating cells of Philadelphia chromosome-positive (Ph+) leukemia cells. Ninety-five percent of chronic myeloid leukemia (CML) cases are Ph+. Ph+ acute lymphoblastic leukemia (ALL) accounts for twenty-five to thirty percent of adult ALL and is considered a high-risk ALL subgroup. Targeting the t(9;22)-fusion protein BCR::ABL1 with ABL1-directed kinase inhibitors (TKIs) is a proven therapeutic concept for CML and Ph+ ALL. Resistance against TKI comprises mutations in BCR::ABL1, but many patients exhibit a primary resistance with unknown mechanisms. Here, we investigated the impact of PROM-1 on the leukemogenesis and the therapy response of Ph+ leukemias. We applied flow cytometry, co-immunoprecipitation, immunoblotting, stem cell assays, and leukemia induction in vivo to cell lines, syngeneic mouse models, and human Ph+ long-term cultures. We found a direct relationship between BCR::ABL1 and PROM-1, a shift from CML towards ALL upon the loss of Prom-1, as well as a link between the response to TKIs and the PROM-1 expression. In contrast to solid tumors, resistance was accompanied by a progressive loss of PROM-1. Our data suggest that PROM-1 plays an essential role in both cell fate decision and induction of the BCR::ABL1-related leukemic phenotype, highlighting its impact on the drug response of Ph+ leukemias. Teaser abstract The Philadelphia chromosome (Ph) is the product of the t(9;22), which fuses the BCR gene on chromosome 22 to the ABL1 gene on chromosome 9. The result is the BCR::ABL1 oncogene, which is responsible for the induction of chronic myeloid leukemia (CML) and for about a third of acute lymphoblastic leukemia (Ph+ ALL). Only little is known about how t(9;22) induces either CML or ALL, and why there is a difference between the two diseases regarding their response to inhibitors that can inactivate BCR::ABL1. Here, we show that a gene called PROMININ-1 is involved in both processes: determining whether BCR::ABL1 induces CML or ALL, and explaining the weaker response of Ph+ ALL compared to CML to inhibitors of BCR::ABL1. We found that the reduction of PROMININ-1 increased the proportion of ALL induced by BCR::ABL1 in the mouse. We could not reproduce these findings in humans but distinguish CML from Ph+ ALL by the expression of PROMININ-1. Also resistance to BCR::ABL1 inhibitors was associated with low expression of PROMININ-1 in Ph+ ALL. These findings are in contrast to observations in solid tumors where a higher level of PROMININ-1 is accompanied by therapy resistance. Our findings contribute to a better understanding of the different types of Ph+ leukemia and their response to therapy, which will help patients better manage these diseases.