Summary Chromosomal translocations affecting Mixed Lineage Leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report development of highly potent and orally bioavailable small molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

SUMMARY Chromosomal translocations involving the mixed lineage leukemia (MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8 deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.

This paper describes the development of a drug rings database and Web-based search tools. The database contains ring structures from both corporate and commercial databases, along with characteristic descriptors including frequency of occurrence as an indicator of synthetic accessibility and calculated property and geometric parameters. Analysis of the rings in several major databases is described, with illustrations of applications of the database in lead discovery programs where bioisosteres and geometric isosteres are sought.

f Congenital dyserythropoietic anemia type II (CDAII) is an autosomal recessive disease of ineffective erythropoiesis characterized by increased bi/multinucleated erythroid precursors in the bone marrow. CDAII results from mutations in SEC23B. The SEC23 protein is a core component of coat protein complex II-coated vesicles, which transport secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Though the genetic defect underlying CDAII has been identified, the pathophysiology of this disease remains unknown. We previously reported that SEC23B-deficient mice die perinatally, exhibiting massive pancreatic degeneration, with this early mortality limiting evaluation of the adult hematopoietic compartment. We now report that mice with SEC23B deficiency restricted to the hematopoietic compartment survive normally and do not exhibit anemia or other CDAII characteristics. We also demonstrate that SEC23B-deficient hematopoietic stem cells (HSC) do not exhibit a disadvantage at reconstituting hematopoiesis when compared directly to wild-type HSC in a competitive repopulation assay. Secondary bone marrow transplants demonstrated continued equivalence of SEC23B-deficient and WT HSC in their hematopoietic reconstitution potential. The surprising discordance in phenotypes between SEC23B-deficient mice and humans may reflect an evolutionary shift in SEC23 paralog function and/or expression, or a change in a specific COPII cargo critical for erythropoiesis.

The energies of the 3da/, and 3da/, levels have been determined for palladium and 13 of its compounds. The measured energies are related t o electronegativity differences between the palladium and the ligand donor atoms except in those cases where the ligand is a ?r acceptor. Ligands which are K acceptors cause greater energy level shifts since they permit greater depletion of electronic charge from the palladium. The energies of the K(2s) and P(2p) levels measured for several complexes were found to be nearly constant. The energy of the Br(3ps/,) level was lowered somewhat when the bromine occupied a bridging position in PdBrZ. The observed shifts can be "explained" by a combination of electronegativity and ?r-bonding effects. T h e cobalt(II1) complex L' = [Co( (C~H~)ZP(CHZ)ZP(C~H;)Z}Z(CN)Z] + acts as positively charged ligand giving compounds of the stoichiometry M(L+)XI, where M = Mn(II), F e ( I I ) , Co(II), N i ( I I ) , or Zn(I1) and X = halogen or pseudohalogen.On the basis of their electronic and vibrational spectra, magnetic susceptibilities, and X-ray diffraction patterns, these compounds zre formulated as pseudotetrahedral zwitterion complexes in which the cobalt(II1) cation is bound to MX3moieties through the nitrogen atom of one cyanide group.

The Cretaceous-Paleogene (K-Pg) boundary is the best known and most widely recognized global time horizon in Earth history and coincides with one of the two largest known mass extinctions. We present a series of new high-precision Uranium-Lead (U-Pb) age determinations by the chemical abrasion isotope dilution thermal ionization mass spectrometry (CA-ID-TIMS) method from volcanic ash deposits within a tightly constrained magnetobiostratigraphic framework across the K-Pg boundary in the Denver Basin, Colorado, USA. This new timeline provides a precise interpolated absolute age for the K-Pg boundary of 66.021 ± 0.024/0.039/0.081 Ma, constrains the ages of magnetic polarity Chrons C28 to C30, and offers a direct and independent test of early Paleogene astronomical and 40 Ar/ 39 Ar based timescales. Temporal calibration of paleontological and palynological data from the same deposits show that the interval between the extinction of the dinosaurs and the appearance of earliest Cenozoic mammals in the Denver Basin lasted ~228 ky (and no more than 570 ky) and the 'fern spike' lasted ~1 ky (and no more than 71 ky) after the K-Pg boundary layer was deposited, indicating rapid rates of biotic extinction and initial recovery in the Denver Basin during this event.

Fluctuations in depositional conditions during the onset of severe climate events in Earth history predispose stratigraphic archives to hiatuses, often hindering complete reconstructions of paleoclimate events and their triggers. Several studies have proposed that a hiatus of unknown duration exists at the base of Oceanic Anoxic Event 2 (OAE2) in the North American Western Interior Basin at the base Turonian global boundary stratotype section and point (GSSP) in Pueblo, Colorado, which potentially influences integrated radioisotopic, biostratigraphic, and astrochronologic age models of the Cenomanian-Turonian boundary interval. To quantify the duration of this hiatus, refine the chronology of OAE2, and assess marine geochemical perturbations associated with the onset of the event, we present new 40Ar/39Ar dates from regional bentonites along with a new proximal-distal chemostratigraphic transect of the epeiric Western Interior Basin (WIB), including initial osmium isotope (Osi) and stable carbon isotope (δ13C) data. The new 40Ar/39Ar age determinations confirm and further constrain previous estimates of Cenomanian-Turonian boundary timing. Further, the regional chemostratigraphic synthesis demonstrates the conformity of the OAE2 successions correlated to Pueblo, shows that the duration of the lag between the onset of the Osi and δ13C excursions is ∼60 k.y., and thus constrains the magnitude of the pre-OAE2 hiatus in Pueblo to less than this value. The new astronomically tuned, conformable Osi record across the onset of OAE2 captures a geologically rapid onset of large igneous province volcanism, consistent with other records, such that the addition of CO2 to the ocean-atmosphere system may have driven changes in marine carbonate chemistry. Additionally, the refined chronostratigraphy of OAE2 and the Cenomanian-Turonian boundary in the central WIB improves correlation with other records, such as those in the Eagle Ford Group, Texas. The correlations highlight that discrepancies among OAE2 age models from globally distributed sections commonly stem from differing definitions of the event and uncertainties associated with astronomical tuning, in addition to stratigraphic preservation.

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