A key characteristic of stem cells and cancer cells is their ability to self-renew. To test if Wnt signaling can regulate the self-renewal of both stem cells and cancer cells in the hematopoietic system, we developed mice that lack beta-catenin in their hematopoietic cells. Here we show that beta-catenin-deficient mice can form HSCs, but that these cells are deficient in long-term growth and maintenance. Moreover, beta-catenin deletion causes a profound reduction in the ability of mice to develop BCR-ABL-induced chronic myelogenous leukemia (CML), while allowing progression of acute lymphocytic leukemia (ALL). These studies demonstrate that Wnt signaling is required for the self-renewal of normal and neoplastic stem cells in the hematopoietic system.

Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.next-generation sequencing | cancer genetics | cancer heterogeneity D iffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults (1). Although nearly half the patients can be cured with standard regimens, the majority of relapsed patients succumb. Thus, there is an urgent need to identify the genetic underpinnings of the disease and to identify novel treatment strategies. Gene expression profiling (2, 3) has uncovered distinct molecular signatures for DLBCL subtypes that have unique biology and prognoses. High-throughput sequencing has provided rich opportunities for the comprehensive identification of the genetic causes of cancer (4-6). Whereas exhaustive portraits of individual cancer genomes are emerging, the degree to which these genomes represent the disease is unclear.We generated a detailed analysis of a DLBCL genome by sequencing a primary human tumor and paired normal tissue (Dataset S1). We further characterized the genetic diversity of DLBCL by sequencing the exomes of 73 DLBCL primary tumors (34 with matched normal DNA) and 21 DLBCL cell lines for comparative purposes. This in-depth sequencing identified 322 DLBCL cancer genes that were recurrently mutated in DLBCLs. We also experimentally validated the effects of genetic alteration of PIK3CD, an oncogene that we identified in DLBCL. Our work provides one of the largest genetic portraits yet of human DLBCLs and offers insights into the molecular heterogeneity of the disease, especially in the context of other recently published studies in DLBCL (7, 8).