Recent advances in chemotherapy and stem cell transplantation have improved survival of pediatric B-ALL patients. Nevertheless, high-risk relapsed or refractory disease remains a challenge and is not curable with chemotherapy alone. One promising strategy to treat B-ALL is to modify patients' own immune cells, empowering them to eliminate B-ALL blasts. For example, autologous cytotoxic T lymphocytes (CTLs) can be engineered ex vivo to express chimeric antigen receptors (CAR) recognizing CD19, a surface antigen expressed on B-ALL blasts. Dozens of children have been infused with CART19 at CHOP, and 80% of them achieved complete responses. The main lesson learned from these trials is that CART19 can be very effective against most (although not all) high-risk B-ALLs.
This surprising effectiveness begs the question of whether other CARs would be equally potent anti-cancer tools or whether CD19 represents a uniquely qualified target. This antigen has been initially chosen because of its broad expression spectrum across B-cell neoplasms and also because of its strictly B-cell lineage-specific expression. Thus, save for normal B-lymphocytes, normal tissues are not affected by CART19. Our recent experimental data indicate that CD19 plays an important role in the pathogenesis of B-cell neoplasms and that lymphomas and leukemias might be under strong selective pressure to retain its expression. Are these oncogenic properties of CD19 key to the success of CART19? This is not merely a basic science question – it pertains to likely mechanisms of relapse and resistance. Would CART19-relapsed tumors have high or low CD19 levels? And which CD19-dependent or –independent pathways could sustain their expansion? Better understanding of the underlying mechanisms will allow us to determine what drugs could be used to either prevent the relapses or treat the relapsed patients.
My laboratory is broadly interested in the mechanisms of neoplastic transformation by the Myc family oncoproteins (including c- and N-Myc). The corresponding genes are altered via chromosomal translocation in B-cell lymphomas and are amplified or otherwise deregulated in many solid malignancies. Yet their exact roles in promoting neoplastic growth in genetically complex human cancers remain only partially understood. The major breakthrough in the field was the discovery of MYC-regulated microRNAs, in particular the miR-17~92 cluster, which is transcriptionally induced by both c- and N-Myc.
Early on, we were able to demonstrate that in solid tumors, such as pediatric neuroblastoma and colon adenocarcinoma, deregulation of miR-17-92 leads to profound suppression of TGFβ signaling and sharply diminished production of many anti-angiogenic factors such as thrombospondin-1 and clusterin (Chayka et al, J Natl Cancer Inst 2009; Dews et al, Cancer Res 2010; Mestdagh et al, Mol Cell 2010, Sundaram et al, Cancer Res 2011, Fox et al, RNA 2013). This brings about robust tumor neovascularization and enhanced neoplastic growth. In fact, our ʽ06 discovery that miR-17~92 augments tumor angiogenesis (Dews et al, Nature Genet 2006) was the first example of the involvement of microRNAs in non-cell-autonomous tumor phenotypes and vascular biology.
To determine the contribution of c-Myc to malignant growth in hematopoietic tissues, we have developed several new mouse models for B-cell lymphoma based on infection of p53-deficient bone marrow progenitors by Myc-encoding retroviruses (Yu et al, Blood 2007; Cozma et al, J Clin Invest 2007; Amaravadi et al, J Clin Invest 2007). Unexpectedly, we discovered that the salient feature of Myc-induced lymphomagenesis was not only overexpression of the oncogenic miR-17-92 but also repression of several tumor suppressive microRNAs, such as miR-15/16 and miR-34 (Chang et al, Nature Genet 2008 & Proc Natl Acad Sci 2009, Sotillo et al, Oncogene 2011). These microRNAs affect c-Myc expression levels and contribute to deregulation of multiple Myc target genes, therapeutic apoptosis and last but not least - B-cell receptor signaling. In the last two years we focused our attention on that last aspect of lymphoma biology. The role of BCR signaling in lymphomagenesis is the focus of our two most recent papers: Chung et al, J Clin Invest 2012, and Psathas et al, Blood 2013.« Back to Previous Page