Date Published: July 28, 2017
Publisher: Public Library of Science
Author(s): Özlem Demirel, Olivier Balló, Pavankumar N. G. Reddy, Olesya Vakhrusheva, Jing Zhang, Astrid Eichler, Ramona Fernandes, Susanne Badura, Hubert Serve, Christian Brandts, Persio Dello Sbarba.
Treatment with tyrosine kinase inhibitors is the standard of care for Philadelphia chromosome positive leukemias. However the eradication of leukemia initiating cells remains a challenge. Circumstantial evidence suggests that the cytokine microenvironment may play a role in BCR-ABL mediated leukemogenesis and in imatinib resistance. Gene expression analyses of BCR-ABL positive ALL long-term cultured cells revealed strong reduction of SOCS mRNA expression after imatinib treatment, thereby demonstrating a strong inhibition of cytokine signaling. In this study we employed SOCS1—a strong inhibitor of cytokine signaling—as a tool to terminate external cytokine signals in BCR-ABL transformed cells in vitro and in vivo. In colony formation assays with primary bone marrow cells, expression of SOCS1 decreased colony numbers under pro-proliferative cytokines, while it conferred growth resistance to anti-proliferative cytokines. Importantly, co-expression of SOCS1 with BCR-ABL led to the development of a MPD phenotype with a prolonged disease latency compared to BCR-ABL alone in a murine bone marrow transplantation model. Interestingly, SOCS1 co-expression protected 20% of mice from MPD development. In summary, we conclude that under pro-proliferative cytokine stimulation at the onset of myeloproliferative diseases SOCS1 acts as a tumor suppressor, while under anti-proliferative conditions it exerts oncogenic function. Therefore SOCS1 can promote opposing functions depending on the cytokine environment.
The reciprocal translocation of chromosomes 9 and 22 [t(9;22)(q34;q11)] generates the so called Philadelphia chromosome harboring the fusion gene BCR-ABL.[1,2] The non-receptor tyrosine kinase c-ABL regulates a variety of cellular processes including cell growth and survival.[3,4] Fusion of BCR upstream to the ABL gene results in a constitutively active tyrosine kinase conferring proliferative advantages and resistance to apoptosis on affected cells. Depending on the breakpoint in the BCR gene, fusion proteins of different sizes are generated, most commonly proteins of 210 kDa (BCR-ABLp210) or 185 kDa (BCR-ABLp185). BCR-ABLp210 is present in about 90% of chronic myeloid leukemia (CML) patients and approximately one third of B-cell acute lymphoid leukemia (B-ALL) patients. On the other hand BCR-ABLp185 is detected in B-ALL leukemia and is rarely found in CML patients. In murine models, over-expression of the respective protein in hematopoietic stem and progenitor cells gives rise to an aggressive myeloproliferative disease (MPD) or leukemia phenotype with very short latency.[8,9] Although development of tyrosine kinase inhibitors (TKI) was a remarkable milestone for the therapy of BCR-ABL positive leukemias, disease persistence and resistance to TKIs are remaining issues. Mutations in the kinase domain[10,11], elevated BCR-ABL levels and increased STAT5 expression are among the reasons causing resistance to TKIs. Recent studies suggest that CML stem cells are not addicted to BCR-ABL and are therefore not eliminated by imatinib. Cytokine support is a crucial factor allowing growth and survival of CML stem cells independent of BCR-ABL activity. Thus, the cytokine microenvironment is an important determinant in BCR-ABL positive leukemia.
Although application of TKIs such as imatinib turned CML from a life-threatening condition to a treatable disease, eradication of leukemia initiating stem cells is still an unsolved problem. One of the factors causing TKI resistance is the cytokine environment that supports growth and survival of CML stem cells irrespective of BCR-ABL activity. In line with this, disruption of the cytokine support in BCR-ABL induced lymphoblastic leukemia enhances sensitivity to imatinib. To further elucidate the function of cytokines in BCR-ABL mediated transformation and leukemogenesis we used SOCS1 as a tool to modulate cytokine signals.