Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous backbone upon which to study genetic variants, candidate targets, small molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from various lineages and ethnicities. Integrating these data with functional characterizations such as drug-sensitivity data, short hairpin RNA knockdown and CRISPR–Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource to accelerate cancer research using model cancer cell lines.

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The prognosis for adults with precursor B-cell acute lymphoblastic leukemia (B-ALL) remains poor, in part from a lack of therapeutic targets. We identified the type I cytokine receptor subunit CRLF2 in a functional screen for B-ALL-derived mRNA transcripts that can substitute for IL3 signaling. We demonstrate that CRLF2 is overexpressed in approximately 15% of adult and high-risk pediatric B-ALL that lack MLL, TCF3, TEL, and BCR/ABL rearrangements, but not in B-ALL with these rearrangements or other lymphoid malignancies. CRLF2 overexpression can result from translocation with the IGH locus or intrachromosomal deletion and is associated with poor outcome. CRLF2 overexpressing B-ALLs share a transcriptional signature that significantly overlaps with a BCR/ABL signature, and is enriched for genes involved in cytokine receptor and JAK-STAT signaling. In a subset of cases, CRLF2 harbors a Phe232Cys gain-offunction mutation that promotes constitutive dimerization and cytokine independent growth. A mutually exclusive subset harbors activating mutations in JAK2. In fact, all 22 B-ALLs with mutant JAK2 that we analyzed overexpress CRLF2, distinguishing CRLF2 as the key scaffold for mutant JAK2 signaling in B-ALL. Expression of WT CRLF2 with mutant JAK2 also promotes cytokine independent growth that, unlike CRLF2 Phe232Cys or ligand-induced signaling by WT CRLF2, is accompanied by JAK2 phosphorylation. Finally, cells dependent on CRLF2 signaling are sensitive to small molecule inhibitors of either JAKs or protein kinase C family kinases. Together, these findings implicate CRLF2 as an important factor in B-ALL with diagnostic, prognostic, and therapeutic implications.uring the past decade, studies using oligonucleotide arrays and high-throughput sequencing have identified several genetic and transcriptional aberrations in B-cell acute lymphoblastic leukemia (B-ALL) (1), leading to three conceptual advances. First, genes involved in normal B-cell development (e.g., PAX5, IKZF1) are frequently mutated in B-ALL (1-3). Second, B-ALL is highly heterogeneous and can exist as multiple, genetically distinct clones within the same individual (1, 4). Third, B-ALL transcriptional profiles cluster based on characteristic chromosomal rearrangements, hereafter defined as rearrangements of TEL, MLL, TCF3, and BCR/ABL (5-8).However, one third of B-ALL cases lack characteristic rearrangements (9). Transcriptional profiles from a subset of these leukemias cluster with profiles from BCR/ABL-expressing B-ALL (3, 5), suggesting that the former harbor cryptic alterations in tyrosine kinase signaling. Supporting this notion, mutations in JAKs were recently identified in a small percentage of pediatric B-ALL and approximately 20% of ALL in children with Down syndrome (10-14).Upon ligand binding to a type I cytokine receptor, JAKs phosphorylate substrates including STATs, which in turn affect the transcription of progrowth and antiapoptotic factors (15). JAK enzymatic activity requires interaction with a cytokine receptor, which is believed to se...

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