Myeloproliferative Neoplasms Transcriptome Reveals Pro-Inflammatory Signature and Enrichment in Peripheral Blood Monocyte-Related Genes.

Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory status. Analyzing public microarray data from polycythemia vera (n = 41), essential thrombocythemia (n = 21), and primary myelofibrosis (n = 9) patients' peripheral blood by in silico approaches, we found that pro-inflammatory and monocyte-related genes were differentially expressed in MPN patients' transcriptome. Genes related to cell activation, secretion of pro-inflammatory and pro-angiogenic mediators, activation of neutrophils and platelets, coagulation, and interferon pathway were upregulated in monocytes compared to controls. Together, our results suggest that molecular alterations in monocytes may contribute to oncoinflammation in MPN.

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

Bioactive Lipids as Chronic Myeloid Leukemia's Potential Biomarkers for Disease Progression and Response to Tyrosine Kinase Inhibitors.

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that expresses the Philadelphia chromosome and constitutively activated Bcr-Abl tyrosine kinase in hematopoietic progenitor cells. Bcr-Abl tyrosine-kinase inhibitors (TKI) do not definitively cure all CML patients. The efficacy of TKI is reduced in CML patients in the blastic phase-the most severe phase of the disease-and resistance to this drug has emerged. There is limited knowledge on the underlying mechanisms of disease progression and resistance to TKI beyond BCR-ABL1, as well as on the impact of TKI treatment and disease progression on the metabolome of CML patients. The present study reports the metabolomic profiles of CML patients at different phases of the disease treated with TKI. The plasma metabolites from CML patients were analyzed using liquid chromatography, mass spectrometry, and bioinformatics. Distinct metabolic patterns were identified for CML patients at different phases of the disease and for those who were resistant to TKI. The lipid metabolism in CML patients at advanced phases and TKI-resistant patients is reprogrammed, as detected by analysis of metabolomic data. CML patients who were responsive and resistant to TKI therapy exhibited distinct enriched pathways. In addition, ceramide levels were higher and sphingomyelin levels were lower in resistant patients compared with control and CML groups. Taken together, the results here reported established metabolic profiles of CML patients who progressed to advanced phases of the disease and failed to respond to TKI therapy as well as patients in remission. In the future, an expanded study on CML metabolomics may provide new potential prognostic markers for disease progression and response to therapy.

Philadelphia-negative myeloproliferative neoplasms display alterations in monocyte subpopulations frequency and immunophenotype.

Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal hematological diseases associated with driver mutations in JAK2, CALR, and MPL genes. Moreover, several evidence suggests that chronic inflammation and alterations in stromal and immune cells may contribute to MPN's pathophysiology. We evaluated the frequency and the immunophenotype of peripheral blood monocyte subpopulations in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). Peripheral blood monocytes from PV (n = 16), ET (n = 16), and MF (n = 15) patients and healthy donors (n = 10) were isolated and submitted to immunophenotyping to determine the frequency of monocyte subpopulations and surface markers expression density. Plasma samples were used to measure the levels of soluble CD163, a biomarker of monocyte activity. PV, ET, and MF patients presented increased frequency of intermediate and non-classical monocytes and reduced frequency of classical monocytes compared to controls. Positivity for JAK2 mutation was significantly associated with the percentage of intermediate monocytes. PV, ET, and MF patients presented high-activated monocytes, evidenced by higher HLA-DR expression and increased soluble CD163 levels. The three MPN categories presented increased frequency of CD56+ aberrant monocytes, and PV and ET patients presented reduced frequency of CD80/86+ monocytes. Therefore, alterations in monocyte subpopulations frequency and surface markers expression pattern may contribute to oncoinflammation and may be associated with the pathophysiology of MPN.