Rabbit Anti-Human NPM Polyclonal Antibody Knockout Validated

Favorable acute myeloid leukemia (AML) patients (pts.) demonstrate a relatively good outcome with standard induction; thus, pts. are generally not addressed to allogeneic transplant in first remission. However, it is not clear if also in a real-life setting, the outcome is homogeneous in the different favorable molecular groups and which are the parameters significantly associated to an increased relapse risk, useful to suggest the need of an intensified approach. In order to clarify this point, we collected clinical data on consecutive unselected AML pts. assigned to favorable category (modified ELN 2010 due to the inclusion of double-mutated CEBPA-positive cases), diagnosed and treated in six centers of the Italian network Rete Ematologica Lombarda (REL) from 2007 to 2015. We assessed response (CR, mCR), relapse rate (CIR), and outcome (OS, DFS) after first-line treatment. A total of 201 pts. was studied and the analysis was performed globally and in each molecular group: t(8;21)(q22;q22)/RUNX1-RUNX1T1 (30 pts., 14.9%), inv. (16)(p13q22) or t(16;16)(p13q22)/CBFB-MIH11 (35 pts., 17.4%), normal karyotype and mutated NPM1 and negative FLT3-ITD (116 pts., 57.7%) or double-mutated CEBPA (CEBPAdm) (20 pts., 10%). Complete remission (CR) was obtained in 188 pts. (93.5%), molecular CR (mCR) in 114 (67.5%); After a median follow-up of 2.4years, cumulative incidence of relapse (CIR) was documented in 78 of 188 responding pts. (41%) after a median time of 11.3months. CIR was higher in the CBFB-MIH11 group, in pts. achieving only a hematological response without mCR (72.1 vs 28.1%, p<0.001), in older pts. and it resulted independently associated with a lower median cytarabine cumulative dose (CCD). Median OS was not reached: after 5years it was 66.3%, and median DFS was 5.3years, both without difference among groups. Molecular CR reached at any time, during or after the end of first-line treatment, was significantly associated with better DFS, and in particular, mCR assessed at the end of treatment was confirmed in multivariate analysis as an independent prognostic factor both for DFS and OS. In conclusion, the present study confirms in a real-life context the overall good prognosis of favorable-risk AML; the achievement of any molecular negativity during first-line treatment, particularly when assessed at the end of treatment, is associated with lower relapse and better survival. Increasing age at diagnosis has a negative prognostic impact, while CCD higher than 18g/sqm is associated with better outcome.

Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (Npm1) as a potential therapeutic target. Genetic ablation of Npm1 significantly attenuated tumor progression in vitro and in vivo. Furthermore, KRAS-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of Npm1 rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support NPM1 as a therapeutic vulnerability in NSCLC. Significance: Epigenome-wide CRISPR knockout screens identify NPM1 as a novel metabolic vulnerability and demonstrate that targeting NPM1 is a new therapeutic opportunity for patients with NSCLC.y