Primary human acute myelogenous leukemia cells release matrix metalloproteases and their inhibitors: release profile and pharmacological modulation.

OBJECTIVES: Angiogenesis seems important for both leukemogenesis and chemosensitivity in acute myelogenous leukemia (AML). Angiogenesis is regulated by the balance between pro- and antiangiogenic cytokines, which also indicates an important role of matrix metalloproteases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteases (TIMPs). We investigated the constitutive release of MMPs and TIMPs for a large group of consecutive AML patients. METHODS: AML cells were cultured in vitro either alone or together with microvascular endothelial cells, and levels of MMPs and TIMPs were determined in culture supernatants. RESULTS: AML cells showed constitutive release of several MMPs and TIMPs. For all patients, detectable MMP-10 release was observed, and most patients showed detectable release of at least one additional MMP, usually MMP-9 or MMP-2. A significant correlation was found between MMP-9 and TIMP-1 release and the release of several CCL and CXCL chemokines. MMP-9 release was higher for AML cells with monocytic differentiation corresponding to the FAB-subtype M4/M5 AML; it was mainly released in its inactive form, but endogenously active MMP-9 could be detected even in the presence of the constitutively released TIMP-1/2. Endothelial cells released relatively high levels of MMP-10, and these levels were further increased by coculture with AML cells. Patients achieving complete hematological remission after only one induction cycle showed relatively low constitutive MMP-2 release. CONCLUSION: We conclude that primary human AML cells show constitutive release of both MMPs and TIMPs, and this release may be important for leukemogenesis and possibly also for chemosensitivity.

Novel variants in Nordic patients referred for genetic testing of telomere-related disorders.

Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.