Park et al describe a novel KLF4-mediated pathway that promotes chromic myeloid leukemia (CML) stem cell (LSC) survival. Deletion of KLF4 in a mouse model of CML decreases LSC survival through repression of Dyrk2, resulting in c-Myc depletion and increased p53 activity.

BackgroundFolate and cobalamin are essential cofactors for homocysteine (HCY) metabolism. Hyperhomocysteinemia, a multifactorial condition, may reflect B vitamin deficiency and is associated with increased risk of cardiovascular disease, thrombosis, and neurodegenerative and chronic gastrointestinal diseases in humans. Hyperhomocysteinemia has been reported in Greyhounds with suspected chronic enteropathy.ObjectivesTo evaluate the frequencies of and the association between hypofolatemia and hyperhomocysteinemia in Greyhounds.AnimalsData and serum samples from 559 Greyhounds.MethodsNested case‐control study. The frequency of hypofolatemia in Greyhounds was determined by a laboratory database search. The relationship between hyperhomocysteinemia (measured by gas chromatography‐mass spectrometry) and hypocobalaminemia and hypofolatemia was evaluated, and its frequency compared between healthy Greyhounds and Greyhounds with thrombosis or chronic diarrhea.ResultsHypofolatemia was identified in 172 of 423 (41%) Greyhounds and was more common in hypo‐ than in normocobalaminemic dogs (49% vs. 35%; P = .0064). Hyperhomocysteinemia was detected in 53 of 78 (68%) of Greyhounds, being more common in hypo‐ than in normofolatemic dogs (88% vs. 59%; P = .0175). All healthy Greyhounds, 21 of 30 (70%) of dogs with chronic diarrhea and 6 of 8 (75%) of those with thrombosis, were hyperhomocysteinemic. Serum HCY concentrations were inversely correlated with serum folate concentration (ρ = −0.28; P = .0386) and were positively associated with serum albumin concentration (ρ = 0.66; P = .0022).Conclusions and Clinical RelevanceHyperhomocysteinemia occurs frequently in the Greyhound population. Its association with hypofolatemia suggests decreased intracellular availability of B vitamins, but the functional implications warrant further investigation. Hyperhomocysteinemia in Greyhounds potentially may serve as a spontaneous canine model to further investigate hyperhomocysteinemia in humans.

No abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric leukemia with a worse prognosis than most frequent B-cell ALL due to a high incidence of treatment failures and relapse. Our previous work showed that loss of the pioneer factor KLF4 in a NOTCH1-induced T-ALL mouse model accelerated the development of leukemia through expansion of leukemia-initiating cells and activation of the MAP2K7 pathway. Similarly, epigenetic silencing of the KLF4 gene in children with T-ALL was associated with MAP2K7 activation. Here, we showed the small molecule 5Z-7-oxozeaenol (5Z7O) induces dose-dependent cytotoxicity in a panel of T-ALL cell lines mainly through inhibition of the MAP2K7-JNK pathway, which further validates MAP2K7 as a therapeutic target. Mechanistically, 5Z7O-mediated apoptosis was caused by the downregulation of regulators of the G2/M checkpoint and the inhibition of survival pathways. The anti-leukemic capacity of 5Z7O was evaluated using leukemic cells from two mouse models of T-ALL and patient-derived xenograft cells generated using lymphoblasts from pediatric T-ALL patients. Finally, a combination of 5Z7O with dexamethasone, a drug used in frontline therapy, showed synergistic induction of cytotoxicity. In sum, we report here that MAP2K7 inhibition thwarts survival mechanisms in T-ALL cells and warrants future pre-clinical studies for high-risk and relapsed patients.

BackgroundMeasuring S100A12 concentrations in serum and feces is a sensitive and specific marker of inflammation, such as seen with chronic gastrointestinal inflammation in people and dogs. Biomarkers of inflammation in cats are currently lacking.ObjectivesWe aimed to analytically cross‐validate the canine S100A12‐ELISA for the measurement of S100A12 in feline specimens.MethodsThe ELISA was analytically validated by assessing dilutional linearity, spiking/recovery, intra‐ and inter‐assay variability. Reference intervals for serum and fecal feline S100A12 concentrations were calculated using samples from healthy cats, and the short‐term biological variation of fecal S100A12 was assessed.ResultsObserved‐to‐expected ratios (O/E) for serial dilutions of serum and fecal extracts ranged from 91%‐159% (mean, 120%) and 100%‐128% (mean, 114%), and for the spiking/recovery method ranged from 106%‐263% (mean, 154%) and 52%‐171% (mean, 112%). Intra‐ and inter‐assay CV% for serum were ≤5.6% and ≤14.0%, and for fecal extracts were ≤3.8% and ≤19.1%, repsectively. RIs for feline serum and fecal S100A12 concentrations were <43 µg/L and < 20 ng/g, respectively. A mild short‐term biologic variation, but large individuality were detected when measuring fecal S100A12 concentrations in healthy cats.ConclusionsThe canine S100A12‐ELISA is accurate, reproducible, and sufficiently linear and precise for the measurement of S100A12 in feline serum and fecal samples. The use of this assay is a reasonable option for the measurement of S100A12 concentrations in feline specimens and provides a basis for the further evaluation of  S100A12 in cats with gastrointestinal disease. Using a population‐based RI for fecal feline S100A12 appears to be of limited value.