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Introduction Myelodysplastic syndromes (MDS) are age-related clonal myeloid neoplasms characterized by ineffective hematopoiesis. Patients with high-risk MDS have a significantly increased incidence of progression into acute myeloid leukemia (AML). The [...], Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with Increased risk of progression to acute myeloid leukemia (AML). The mechanisms of transformation of MDS to AML are poorly understood, especially in relation to the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with oversecretion of proinflammatory cytokines. Here, we found that most of the DKO mice underwent leukemic transformation at 12-14 months of age. These mice showed myeloblast replacement of fibrotic bone marrow and widespread leukemic infiltration. Strikingly, depletion of IL-6 in these mice largely rescued the leukemic transformation and markedly extended survival. Single-cell RNA sequencing analyses revealed that DKO leukemic mice had increased monocytic blasts that were reduced with IL-6 knockout. We further revealed that the levels of surface and soluble IL-6 receptor (IL-6R) in the bone marrow were significantly increased in high-risk MDS patients. Similarly, IL-6R was also highly expressed in older DKO mice. Blocking of IL-6 signaling significantly ameliorated AML progression in the DKO model and clonogenicity of CD34-positive cells from MDS patients. Our study establishes a mouse model of progression of age-related MDS to AML and indicates the clinical significance of targeting IL-6 signaling in treating high-risk MDS.

In pastoral society, the reproduction of livestock is directly related to the survival and prosperity of herders. The key to domestic animal reproduction lies in the cognitive bond between mother livestock and their young. Herdsmen use various tools and techniques to help develop this cognitive bond. These human mediation tools have various characteristics such as 'restorative' or 'destructive'. The lamb bag, a widely used tool in pastoral society, has both 'restorative' and 'destructive' natures. Based on ethnographic data collected in Inner Mongolia, China, this paper first introduces the production method of lamb bags, then describes their structure, function and the multi-dimensional relationships generated during the application process, and finally discusses the cultural implications of 'restorative' and 'destructive' human mediation in pastoral culture. [ABSTRACT FROM AUTHOR]

ATM deletions and/or mutations are recurrent in lymphoid neoplasms while rearrangements are rare. In this study, we used mate pair sequencing (MPseq) technology to characterize two novel ATM rearrangements in one patient with chronic lymphocytic leukemia (CLL) and one patient with T-prolymphocytic leukemia (T-PLL). Both patients showed chromosome 11q22 aberrations encompassing ATM by conventional karyotype and fluorescence in situ hybridization: isolated t(11;13)(q22;q14) in CLL and a complex karyotype with apparent 11q deletion and unbalanced der(14)t(11;14)(q22;p11.2) in T-PLL. MPseq identified ATM-LINC00371 fusion in CLL and ATM-USP28 in T-PLL, both of which led to ATM inactivation, confirmed by loss of immunohistochemical protein expression. Next-generation sequencing mutation analysis detected concurrent ATM mutation(s) CLL patient, while T-PLL lacked ATM mutation. ATM rearrangements, not apparently detectable using standard laboratory technologies, represent another mechanism of loss-of-function. Recent high-throughput technologies such as MPseq can uncover novel pathogenic gene fusions and resolve complex chromosomal rearrangements in hematologic malignancies. [ABSTRACT FROM AUTHOR]