Chromosome 19 has the highest gene density of all human chromosomes, more than double the genome-wide average. The large clustered gene families, corresponding high G1C content, CpG islands and density of repetitive DNA indicate a chromosome rich in biological and evolutionary significance. Here we describe 55.8 million base pairs of highly accurate finished sequence representing 99.9% of the euchromatin portion of the chromosome. Manual curation of gene loci reveals 1,461 protein-coding genes and 321 pseudogenes. Among these are genes directly implicated in mendelian disorders, including familial hypercholesterolaemia and insulin-resistant diabetes. Nearly one-quarter of these genes belong to tandemly arranged families, encompassing more than 25% of the chromosome. Comparative analyses show a fascinating picture of conservation and divergence, revealing large blocks of gene orthology with rodents, scattered regions with more recent gene family expansions and deletions, and segments of coding and non-coding conservation with the distant fish species Takifugu.

We have determined the full protein kinase (PK) complement (kinome) of mouse. This set of 540 genes includes many novel kinases and corrections or extensions to >150 published sequences. The mouse has orthologs for 510 of the 518 human PKs. Nonorthologous kinases arise only by retrotransposition and gene decay. Orthologous kinase pairs vary in sequence conservation along their length, creating a map of functionally important regions for every kinase pair. Many species-specific sequence inserts exist and are frequently alternatively spliced, allowing for the creation of evolutionary lineage-specific functions. Ninetyseven kinase pseudogenes were found, all distinct from the 107 human kinase pseudogenes. Chromosomal mapping links 163 kinases to mutant phenotypes and unlocks the use of mouse genetics to determine functions of orthologous human kinases. E ukaryotic protein kinases (PKs) constitute one of the largest of mammalian gene families and are key regulators of a wide variety of conserved cellular processes including cell cycle, cell growth and death, metabolism, transcription, morphology and motility, and differentiation. By adding phosphate groups to substrate proteins, kinases alter the activity, location, and lifetime of a large fraction of proteins and coordinate complex cellular functions. Most PKs belong to a single superfamily containing a conserved eukaryotic PK (ePK) catalytic domain. The remaining, atypical PKs (aPKs), for the most part lack sequence similarity to the ePK domain but are known to have catalytic activity. Fifty-one distinct kinase subfamilies are conserved from yeast to human, reflecting the ancient diversity of kinase functions (1). The recent publication of a comprehensive catalog of 518 human kinases (2) includes scores of novel or poorly understood kinases. The draft mouse genome now provides a key to better understand each human kinase, by comparative analysis of protein and regulatory DNA sequences, and by use of mouse genetics and functional assays to probe the shared functions of mouse kinases and their human orthologs. The detailed comparison of such a large superfamily also casts light on the current state and utility of the draft mouse genome.The Ϸ70 million years that separate mouse from human have allowed evolution to test the functional effect of mutations throughout the sequence of every gene. This allows a mapping of functionally important conserved regions within most genes. Initial analysis of the mouse genome (3) showed that within protein coding regions, synonymous nucleotide substitutions (those that do not change protein sequence) occur at a rate [synonymous substitution rate (Ks)] of Ϸ0.6 substitutions per base between mouse and human orthologs, whereas nonsynonymous substitutions are selectively reduced, to a rate [nonsynonymous substitution rate (Ka)] of Ϸ0.01-0.1 per base, indicating that most protein sequence changes are rejected by evolution. Accordingly, protein sequence conservation ranges from an average of 71% for regions outside of known domains, to 9...

The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the signifi cant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the fi rst selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.

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Mouse double minute 2 (MDM2) is a critical negative regulator of the tumor suppressor p53, playing a key role in controlling its transcriptional activity, protein stability, and nuclear localization. MDM2 expression is up-regulated in numerous cancers, resulting in a loss of p53-dependent activities, such as apoptosis and cell-cycle arrest. Genetic amplification and inheritance of MDM2 promoter single-nucleotide polymorphisms (SNPs) are the two best-studied mechanisms for up-regulating MDM2 activity. This article provides an overview of these events in human cancer, highlighting the frequent occurrence of MDM2 amplification in sarcoma and the role of SNP309 and SNP285 in regulating MDM2 expression and cancer risk. The availability of large-scale genomic profiling datasets, like those from The Cancer Genome Atlas Research Network, have provided the opportunity to evaluate the consequences of MDM2 amplification and SNP inheritance across high-quality tumor samples from diverse cancer indications.