Is allogeneic stem cell transplantation for myelofibrosis still indicated at the time of molecular markers and JAK inhibitors era?

OBJECTIVE: The role of allogenic stem cell transplantation (ASCT) is still debated in myelofibrosis (MF). METHODS: A retrospective analyzed was performed to compare the outcome of 71 patients with intermediate-2 or high-risk Dynamic International Prognosis Scoring System+ (DIPSS+) primary (PMF) or secondary (SMF) myelofibrosis with an indication of ASCT as they ultimately underwent the procedure (n=34) or not (n=37). RESULTS: Five-year overall survival (OS) was not statistically different between both groups (allograft: 52% vs no allograft: 34%, P=.12). However, progression to myelodysplastic syndrome or acute myeloid leukemia at 5 years was significantly lower in transplanted patients (14% vs 50%, P=.01). In univariate analysis, 5-year OS was significantly higher for transplanted vs non-transplanted patients with unfavorable karyotype (75% vs 0%, P=.001), SMF (71% vs 20%, P=.001) or high DIPSS+ score (46% vs 15%, P=.03). There was also a trend for better 5-year OS in allografted patients with high JAK2V617F burden (>65%) (75% vs 8%, P=.07). Interestingly, the survival of patients who did not proceed to ASCT was dramatically increased by the use of ruxolitinib. CONCLUSIONS: Not all intermediate-2/high-risk DIPSS+ MF patients benefit from ASCT, especially since the introduction of JAK2 inhibitors.

ENOX2 NADH Oxidase: A BCR-ABL1-Dependent Cell Surface and Secreted Redox Protein in Chronic Myeloid Leukemia

Objective: Chronic myeloid leukemia (CML) is a disease caused by the acquisition of BCR-ABL1 fusion in hematopoietic stem cells. In this study, we focus on the oncofetal ENOX2 protein as a potential secretable biomarker in CML. Materials and Methods: We used cell culture, western blot, quantitative RT-PCR, ELISA, transcriptome analyses, and bioinformatics techniques to investigate ENOX2 mRNA and protein expression. Results: Western blot analyses of UT-7 and TET-inducible Ba/F3 cell lines demonstrated the upregulation of the ENOX2 protein. BCR-ABL1 was found to induce ENOX2 overexpression in a kinase-dependent manner. We confirmed increased ENOX2 mRNA expression in a cohort of CML patients at diagnosis. In a series of CML patients, ELISA assays showed a highly significant increase of ENOX2 protein levels in the plasma of patients with CML compared to controls. Reanalyzing the transcriptomic dataset confirmed ENOX2 mRNA overexpression in the chronic phase of the disease. Bioinformatic analyses identified several genes whose mRNA expressions were positively correlated with ENOX2 in the context of BCR-ABL1. Some of them encode proteins involved in cellular functions compatible with the growth deregulation observed in CML. Conclusion: Our results highlight the upregulation of a secreted redox protein in a BCR-ABL1-dependent manner in CML. The data presented here suggest that ENOX2, through its transcriptional mechanism, plays a significant role in BCR-ABL1 leukemogenesis.

Experimental and integrative analyses identify an ETS1 network downstream of BCR-ABL in chronic myeloid leukemia (CML).

The BCR-ABL oncogene, the hallmark of chronic myeloid leukemia (CML), has been shown to activate several signaling pathways in leukemic cells. The natural history of this disease has been radically modified by tyrosine kinase inhibitors (TKIs). However, resistance to several lines of TKI therapies and progression to blast crisis (BC) remain significant concerns. To identify novel signaling pathways induced by BCR-ABL, we performed a transcriptome analysis in a BCR-ABL-expressing UT-7 cell line. More than 2000 genes differentially expressed between BCR-ABL-expressing and parental UT-7 cells were identified and ETS1 was found to be the most upregulated. ETS1 protein expression was also shown to be highly increased in UT-7 cells expressing BCR-ABL either constitutively or under the control of TET-inducible promoters. ETS1 expression is tyrosine-kinase dependent because it was reduced by TKIs. A significant increase of ETS1 messenger RNA (mRNA) expression was observed in blood cells from CML patients at diagnosis compared with healthy controls. Integration of publicly available chromatin immunoprecipitation sequencing and transcriptomic data with our results allowed us to identify potential ETS1 targets, some of which are involved in the progression of CML. The messenger RNA expression of two of these genes (DNM3 and LIMS1) was found to be associated with the absence of major cytogenetic response after 1 year of imatinib therapy. The present work demonstrates for the first time the involvement of the ETS1 transcriptional program in the experimental UT-7 model and a large cohort of CML patients.