No abstract

CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2;Flt3 AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.

No abstract

New U-Pb zircon, Nd-Sm, and Sr isotopic data from Gander Zone basement fragments in northern New Brunswick, combined with a review of existing data, support a basement-cover relationship between the Avalonian Bras d'Or-Brookville belt and lower Paleozoic clastic rocks of the Gander Zone. Basement fragments occur as (1) large foliated and unfoliated granodiorite cobbles in a late Arenig to Llanvirn conglomerate of the Vallée Lourdes Formation of the Tetagouche Group and (2) as an allochthonous gabbro sheet (Upsalquitch gabbro), tectonically emplaced on top of the Tetagouche Group during Late Ordovician or Early Silurian thrusting.The granodiorite cobbles of the Vallée Lourdes Formation yielded late Mesoproterozoic (ca. 1.09 Ga) U-Pb zircon crystallization ages and gave an ε Nd (T) of -3.47 and a depleted mantle model age (T DM ) of 2.0 Ga. Xenocrystic zircon grains in the cobbles range in age between ca. 1.16 and 1.55 Ga. Geochemical data from a foliated granodiorite cobble suggest that the magma from which it crystallized formed by mixing of mantle-derived and older (>1.5 Ga) crustal-derived components.The Upsalquitch gabbro has a U-Pb zircon crystallization age of 543 +1/-2 Ma (earliest Cambrian) and is inferred to represent a fragment of the Gander Zone basement. Similar age igneous rocks occur in the Avalonian Bras d'Or-Brookville belt. The Upsalquitch gabbro forms the immediate base to one of the Middle Ordovician basalt suites of the Fournier Group (ca. 464 Ma), which indicates the presence of a significant hiatus. The Fournier Group was deposited in a back-arc basin that formed by splitting a late Arenig magmatic arc built on the Gander Zone. During rifting of the arc the gabbroic basement fragment was tectonically exhumed onto the sea floor by low-angle normal faulting immediately before eruption of the basalts. The gabbro's geochemistry indicates that it was mainly derived from a depleted mantle source. Xenocrystic zircons (ca. 2.6 Ga) in the Upsalquitch gabbro suggest the involvement of old Archean crust, although the presence of the latter is not reflected in the Nd-and Sr-isotopic data.The ages presented in this chapter complement detrital and xenocrystic zircon studies carried out by others in the Gander Zone of New Brunswick and Newfoundland and together indicate that basement to the Gander Zone is mainly made up of Early Cambrian (0.54-0.55 Ga), Neoproterozoic (0.6-0.8 Ga), Mesoproterozoic (1.0-1.55 Ga), and Archean rocks (2.5-2.7 Ga). This range of ages, combined with the isotopic and geochemical data, eliminates Laurentia as a possible basement to the

In previous studies, the ability of the hydrodioxyl (perhydroxyl) radical [HOO., the conjugate acid of superoxide (O2.-] to "nick" DNA under biomimetic conditions was demonstrated, and a sequence selectivity was observed. A background level of nonspecific nicking also was noted. This paper provides support for 5'-hydrogen atom abstraction from the deoxyribose ring as the initial event in the sequence-selective nicking by 02.-/HOO.. Two experiments support the proposed mechanism. First, using a defined sequence 5'-32P-labeled restriction fragment as the DNA substrate, only free (unalkylated) 3'-phosphate is produced at the site of nicking. Second, using poly (dA).poly (T) as the substrate, furfural is formed in the reaction from deoxyribose ring breakdown. Both results are consistent with 5'-hydrogen atom abstraction for initiation of the site-selective nicking. Hydrogen atom abstraction at other sites of the deoxyribose ring and/or base oxidation and loss followed by strand scission likely are responsible for the nonspecific nicking. The 5'-abstraction mechanism contrasts to those elicited by other 02-derived and metal-associated oxidants, which may provide a biomarker for the reactivity of HOO. in vivo.