Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD leukemia cells. This synergized with the allogeneic CD8 T cell response, leading to long-term survival in six mouse models of FLT3-ITD AML. Sorafenib-related IL-15 production caused an increase in CD8CD107aIFN-γ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

SummaryETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, and the impact of oncogenes is cell-context dependent, we hypothesized that the childhood affiliation of ETV6-RUNX1 cALL reflects its origins in a progenitor unique to embryonic life. We characterize the first emerging B cells in first-trimester human embryos, identifying a developmentally restricted CD19−IL-7R+ progenitor compartment, which transitions from a myeloid to lymphoid program during ontogeny. This developmental series is recapitulated in differentiating human pluripotent stem cells (hPSCs), thereby providing a model for the initiation of cALL. Genome-engineered hPSCs expressing ETV6-RUNX1 from the endogenous ETV6 locus show expansion of the CD19−IL-7R+ compartment, show a partial block in B lineage commitment, and produce proB cells with aberrant myeloid gene expression signatures and potential: features (collectively) consistent with a pre-leukemic state.

Twenty-one patients with lateral compartment osteoarthritis and valgus deformity of the knee underwent distal femoral supracondylar osteotomy (medial closing wedge) between 1 983 and 1 993 with followup ranging from 1 to 8 years. Ten knees had plastercast immobilization, 5 had fixation with 2 staples supplemented with a plaster cast, and 6 knees had rigid internai fixation with an AO blade plate. Thirty-three percent of patients had a satisfactory result using the HSS score, and 57% had a satisfactory result using the Knee Society Clinical Rating. Fifty-seven percent had a significant complication, including severe knee stiffness requiring manipulation under anesthesia (48%), nonunion/delayed union (19%), infection (1 0%), and fixation failure (5%). Five (1 9%) knees required total knee replacement within 5 years of surgery. Satisfactory results were obtained only in those patients who had less severe degrees of osteoarthritis confined to the lateral compartment (grades I to III), adequate correction of valgus deformity (the anatomical axis within 2° from zero), and rigid internal fixation to permit postoperative early mobilization. These results indicate that distal femoral osteotomy is a satisfactory procedure in the young, active patient with osteoarthritis of the lateral compartment of the knee, but requires precise surgical technique and rigid internal fixation.

The CHK1 Inhibitor MK8776 Selectively Kills EZH2-Defi cient T-ALL CellsTo investigate synthetic lethal interactions that could be exploited in PRC2 defi cient T-ALL, we generated isogenic Jurkat T-ALL cells using a double-nicking CRISPR/Cas9 strategy targeting exon 2 of EZH2, an approach that minimizes off-target effects ( 17 ). We generated two clones with bialellic frameshift mutations in EZH2 (EZH2-KO1 and EZH2-KO2) that resulted in loss of EZH2 protein expression and a global absence of its functional mark H3K27me3 ( Fig. 1A and B ;Research.

SummaryFollowing reduced intensity-conditioned allogeneic stem cell transplantation (RIC allo-SCT) for chronic lymphocytic leukaemia (CLL), there is an inverse relationship between relapse and extensive chronic graft-versus-host disease (GVHD). We evaluated outcomes in 50 consecutive patients with CLL using the approach of alemtuzumab-based RIC allo-SCT and preemptive donor lymphocyte infusions (DLI) for mixed chimerism or minimal residual disease (MRD), with the intention of reducing the risk of GVHD. Forty two patients had high-risk disease, including 30% with 17p deletion (17pÀ). Of patients who were not in complete remission (CR) entering transplant, 83% subsequently achieved MRD-negative CR. Both MRD detection and uncorrected mixed chimerism were associated with greater risks of treatment failure. Nine of sixteen patients receiving DLI for persistent or relapsed disease subsequently attained MRD-negative CR. With a median follow-up of 4Á3 years, 4-year current progression-free survival was 65% and overall survival was 75% (60% and 61% in respectively, patients with 17pÀ). DLI was associated with a 29% cumulative incidence of severe GVHD and mortality of 6Á4%. At last follow-up, 83% of patients in CR were off all immunosuppressive treatment. In conclusion, the directed delivery of allogeneic cellular therapy has the potential to induce durable remissions in high-risk CLL without incurring excessive GVHD.