Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph plus ) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665

Recent studies have identified oncogenic lesions in Philadelphia chromosome-positive (Ph+)  acute lymphoblastic leukemia (ALL) and ABL1 kinase mutations that confer resistance to tyrosine kinase inhibitors. We sought to determine the prevalence and clinical impact of these lesions in patients on CALGB 10001, a previously reported Phase II study of imatinib, chemotherapy, and hematopoietic cell transplant in adult Ph + ALL. Of the 58 enrolled, 22 relapsed. By direct sequencing, an ABL1 kinase mutation known to induce imatinib resistance was present at relapse in 13 of 20. Using quantitative PCR assays, the mutations were detectable at diagnosis or early during treatment in most (62%) relapsed patients. Aberrations in IKZF1, CDKN2A/B, and PAX5 were assessed in 28 samples using SNP arrays and genomic DNA sequencing. Of these, 22 (79%) had IKZF1 deletion. The combination of IKZF1 deletion and p210 BCR-ABL1 (p < 0.0001), high white blood cell count (p = 0.021), and minimal residual disease (p = 0.013) were associated with worse disease-free survival.Rebecca DeBoer, Gregory Koval, Flora Mulkey, Meir Wetzler, Steven Devine, Guido Marcucci, Richard M. Stone, Richard A. Larson, Clara D. Bloomfield, Susan Geyer, Charles G. Mullighan and Wendy Stoc

Calcineurin, a Calcium/Calmodulin-dependent Protein Phosphatase, Is Involved in Movement, Fertility, Egg Laying, and Growth in Caenorhabditis elegans

Calcineurin is a Ca(2+)-calmodulin–dependent serine/threonine protein phosphatase that has been implicated in various signaling pathways. Here we report the identification and characterization of calcineurin genes in Caenorhabditis elegans (cna-1 and cnb-1), which share high homology with Drosophila and mammalian calcineurin genes. C. elegans calcineurin binds calcium and functions as a heterodimeric protein phosphatase establishing its biochemical conservation in the nematode. Calcineurin is expressed in hypodermal seam cells, body-wall muscle, vulva muscle, neuronal cells, and in sperm and the spermatheca. cnb-1 mutants showed pleiotropic defects including lethargic movement and delayed egg-laying. Interestingly, these characteristic defects resembled phenotypes observed in gain-of-function mutants of unc-43/Ca(2+)-calmodulin–dependent protein kinase II (CaMKII) and goa-1/G(o)-protein α-subunit. Double mutants of cnb-1 and unc-43(gf) displayed an apparent synergistic severity of movement and egg-laying defects, suggesting that calcineurin may have an antagonistic role in CaMKII-regulated phosphorylation signaling pathways in C. elegans

Fathers\u27 and Mothers\u27 Cognitive Stimulation in Early Play with Toddlers: Predictors of 5th grade Reading and Math

Developmental support in early parent-infant interactions has been shown to predict children\u27s early development and later academic success, but the long-term combined impacts of maternal and paternal interactions are rarely examined. For 229 low-income children in the US Early Head Start Research and Evaluation Project, parent-toddler interactions at age 2, observed separately with fathers and mothers, were examined in relation to child outcomes at age 3 and 5th grade. In families with resident biological fathers, both mother and father cognitive stimulation independently predicted 5th grade math and reading, over and above program impacts and child gender. In other families, only mother cognitive stimulation predicted later child outcomes, even if fathers were involved in children\u27s lives. Adding early developmental indicators to the model showed that the contributions of mothers\u27 early cognitive stimulation on children\u27s later academic skills were significantly mediated by children\u27s early development in biological father-resident families, but not in other families. Similarly, adding early developmental indicators to the reading model showed that the contributions of fathers\u27 early cognitive stimulation on children\u27s later reading was partially mediated by children\u27s early vocabulary in biological father-resident families, but not in other families. These results suggest that fathers\u27 and mothers\u27 cognitive stimulation in early play with toddlers both have the potential to make long-term direct and indirect impacts on their children\u27s academic success