[Philadelphia chromosome-negative myeloid neoplasms in patients with Philadelphia chromosome-positive chronic myeloid leukemia during tyrosine kinase inhibtor-therapy].

Objective: To compare the clinical features between the 2 cohorts developing myelodysplastic syndrome or acute myeIogenous Ieukemia in Philadelphia chromosome-negative cells (Ph(-) MDS/AML) and maintaining disease stable in the patients with Philadelphia chromosome-positive chronic myeloid Ieukemia (Ph(+) CML) who had clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph(-)) during tyrosine kinase inhibtor (TKI) - therapy. Methods: We retrospectively analyzed Ph(+) CML patients who developed CCA/Ph(-) during TKI-therapy from May 2001 to December 2017. Results: Data of CCA/Ph(-) 63 patients, including 7 progressing to Ph(-) MDS/AML and 56 remaining disease stable were collected. Compared with those with stable disease, patients with Ph(-)MDS/AML had lower hemoglobin (P=0.007) and platelet (P=0.006) counts, and higher proportion of peripheral blasts (P<0.001) when the first time CCA/Ph(-) was detected, and more mosonomy 7 abnormality (5/7, 71.4%) when MDS or AML was diagnosed; meanwhile, trisomy 8 (32/56, 57.1%) was more common in those with stable disease. Outcome of the patients with Ph(-) MDS/AML were poor. However, most of those with CCA/Ph(-) and stable disease had optimal response on TKI-therapy. Conclusions: A few patients with Ph(+) CML developed CCA/Ph(-) during TKI-therapy, most of them had stable disease, but very few patients developed Ph(-) MDS/AML with more common occurrence of monosomy 7 or unknown cytopenia. Our data suggested the significance of monitoring of peripheral blood smear, bone marrow morphology and cytogenetic analysis once monosomy 7 or unknown cytopenia occurred.

Philadelphia chromosome-negative myeloid neoplasms in patients with Philadelphia chromosome-positive chronic myeloid leukemia during tyrosine kinase inhibtor-therapy / 中华血液学杂志

Objective@#To compare the clinical features between the 2 cohorts developing myelodysplastic syndrome or acute myeIogenous Ieukemia in Philadelphia chromosome-negative cells (Ph- MDS/AML) and maintaining disease stable in the patients with Philadelphia chromosome-positive chronic myeloid Ieukemia (Ph+ CML) who had clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph-) during tyrosine kinase inhibtor (TKI) - therapy.@*Methods@#We retrospectively analyzed Ph+ CML patients who developed CCA/Ph- during TKI-therapy from May 2001 to December 2017.@*Results@#Data of CCA/Ph- 63 patients, including 7 progressing to Ph- MDS/AML and 56 remaining disease stable were collected. Compared with those with stable disease, patients with Ph-MDS/AML had lower hemoglobin (P=0.007) and platelet (P=0.006) counts, and higher proportion of peripheral blasts (P<0.001) when the first time CCA/Ph- was detected, and more mosonomy 7 abnormality (5/7, 71.4%) when MDS or AML was diagnosed; meanwhile, trisomy 8 (32/56, 57.1%) was more common in those with stable disease. Outcome of the patients with Ph- MDS/AML were poor. However, most of those with CCA/Ph- and stable disease had optimal response on TKI-therapy.@*Conclusions@#A few patients with Ph+ CML developed CCA/Ph- during TKI-therapy, most of them had stable disease, but very few patients developed Ph- MDS/AML with more common occurrence of monosomy 7 or unknown cytopenia. Our data suggested the significance of monitoring of peripheral blood smear, bone marrow morphology and cytogenetic analysis once monosomy 7 or unknown cytopenia occurred.

Philadelphia chromosome-negative myeloid neoplasms in patients with Philadelphia chromosome-positive chronic myeloid leukemia during tyrosine kinase inhibtor-therapy / 中华血液学杂志

Objective: To compare the clinical features between the 2 cohorts developing myelodysplastic syndrome or acute myeIogenous Ieukemia in Philadelphia chromosome-negative cells (Ph(-) MDS/AML) and maintaining disease stable in the patients with Philadelphia chromosome-positive chronic myeloid Ieukemia (Ph(+) CML) who had clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph(-)) during tyrosine kinase inhibtor (TKI) - therapy. Methods: We retrospectively analyzed Ph(+) CML patients who developed CCA/Ph(-) during TKI-therapy from May 2001 to December 2017. Results: Data of CCA/Ph(-) 63 patients, including 7 progressing to Ph(-) MDS/AML and 56 remaining disease stable were collected. Compared with those with stable disease, patients with Ph(-)MDS/AML had lower hemoglobin (P=0.007) and platelet (P=0.006) counts, and higher proportion of peripheral blasts (P<0.001) when the first time CCA/Ph(-) was detected, and more mosonomy 7 abnormality (5/7, 71.4%) when MDS or AML was diagnosed; meanwhile, trisomy 8 (32/56, 57.1%) was more common in those with stable disease. Outcome of the patients with Ph(-) MDS/AML were poor. However, most of those with CCA/Ph(-) and stable disease had optimal response on TKI-therapy. Conclusions: A few patients with Ph(+) CML developed CCA/Ph(-) during TKI-therapy, most of them had stable disease, but very few patients developed Ph(-) MDS/AML with more common occurrence of monosomy 7 or unknown cytopenia. Our data suggested the significance of monitoring of peripheral blood smear, bone marrow morphology and cytogenetic analysis once monosomy 7 or unknown cytopenia occurred.

Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation.

Ponatinib is a multi-targeted third generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia (CML) patients harboring the Abelson (Abl)-breakpoint cluster region (Bcr) T315I mutation. In spite of having superb clinical efficacy, ponatinib triggers severe vascular adverse events (VAEs) that significantly limit its therapeutic potential. On vascular endothelial cells (ECs), ponatinib promotes EC dysfunction and apoptosis, and inhibits angiogenesis. Furthermore, ponatinib-mediated anti-angiogenic effect has been suggested to play a partial role in systemic and pulmonary hypertension via inhibition of vascular endothelial growth factor receptor 2 (VEGFR2). Even though ponatinib-associated VAEs are well documented, their etiology remains largely unknown, making it difficult to efficiently counteract treatment-related adversities. Therefore, a better understanding of the mechanisms by which ponatinib mediates VAEs is critical. In cultured human aortic ECs (HAECs) treated with ponatinib, we found an increase in nuclear factor NF-kB/p65 phosphorylation and NF-kB activity, inflammatory gene expression, cell permeability, and cell apoptosis. Mechanistically, ponatinib abolished extracellular signal-regulated kinase 5 (ERK5) transcriptional activity even under activation by its upstream kinase mitogen-activated protein kinase kinase 5α (CA-MEK5α). Ponatinib also diminished expression of ERK5 responsive genes such as Krüppel-like Factor 2/4 (klf2/4) and eNOS. Because ERK5 SUMOylation counteracts its transcriptional activity, we examined the effect of ponatinib on ERK5 SUMOylation, and found that ERK5 SUMOylation is increased by ponatinib. We also found that ponatibib-mediated increased inflammatory gene expression and decreased anti-inflammatory gene expression were reversed when ERK5 SUMOylation was inhibited endogenously or exogenously. Overall, we propose a novel mechanism by which ponatinib up-regulates endothelial ERK5 SUMOylation and shifts ECs to an inflammatory phenotype, disrupting vascular homeostasis.