Adam Lerner, MD
|PI: Adam Lerner, MD
Title: Professor of Medicine, PI and Director of Hematology Training Program
1) Cyclic nucleotide phosphodiesterases (PDEs) as therapeutic targets in human lymphoid malignancies. We have found that inhibition of the PDE4 cAMP PDE family induces apoptosis in primary leukemic cells from patients with B-CLL. In the absence of exogenous stimulation of adenylate cyclase, addition of a PDE4 inhibitor activates both PKA and EPAC, a cAMP-activated Rap1 GDP exchange factor. Surprisingly, expression of EPAC is unique to B-CLL among circulating hematopoietic cells and activation of EPAC is anti-apoptotic, suggesting that it may play a pathophysiologic role in this disease. PDE4 inhibitors confer their most dramatic apoptotic effects in conjunction with either radiation or glucocorticoids such as dexamethasone. PDE4 inhibitor-mediated PKA activation in primary human B-CLL cells increases levels of glucocorticoid receptor and augments glucocorticoid-induced GRE transactivation. Inhibition of PKA blocks glucocorticoid-mediated apoptosis in CLL. Our current focus is on elucidating the role of PDE4 inhibitors in modulating Toll receptor signaling in normal and malignant lymphoid cells.
2) The role of the BCAR3/NSP family in human epithelial tumors. We cloned AND-34/BCAR3 and demonstrated that it associates with the focal adhesion adapter protein p130Cas and that over-expression of BCAR3 activates the small GTPases Rac and Cdc42. In an unbiased study of initially antiestrogen-sensitive breast cancer cell lines, Dorserrs et al determined that over-expression of BCAR3 or p130Cas induced resistance to the clinically important antiestrogens tamoxifen and faslodex. Among three highly related gene family members, only BCAR3 induces anti-estrogen resistance as well as cyclin D1 promoter activation. BCAR3 over-expression leads to Rac activation as a result of its ability to activate PI3K, but such Rac activation is not sufficient for anti-estrogen resistance as all three gene family members activate Rac. Among NSP family members, only AND-34 induces p130Cas serine phosphorylation (Cellular Signaling 2009: 21:1423-35). Our AND-34 knockout mouse shows rupture of the ocular lens shortly after birth (Molecular Vision 2009;15:685-699). Our most recent work demonstrates that by binding to p130Cas, BCAR3 alters p130Cas such that it binds the SH3 domain of Src, facilitating Src-mediated tyrosine phosphorylation of p130Cas and downstream signaling (JBC 2012, 273:27703).
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Cai D, Felekkis K,Near R,Iyer A,O’Neill G,Seventer J,Golemis E ,Lerner A. The GDP exchange factor AND-34 is expressed in B cells, associates with HEF1, and activates Cdc42. J. Immunol. 2003, 170:969-978 (PMID: 12517963).
Cai D, Iyer A, Near RI, Felekkis KN, Luo Z, Albanese C, Pestell RG and Lerner A. AND-34/BCAR3, a GDP exchange factor whose over-expression confers antiestrogen resistance, activates Rac1, Pak1 and the cyclin D1 promoter. Cancer Research 2003, 63:6802-6808 (PMID: 14583477).
Moon E and Lerner A. PDE4 inhibitors activate a mitochondrial apoptotic pathway in chronic lymphocytic leukemia that is regulated by PP2A. Blood 2003;101:4122-4130 (PMID: 12531792).
Tiwari S, Felekkis K, Moon E-Y, Flies A, Sherr D, Lerner A. Among circulating hematopoietic cells, B-CLL uniquely expresses functional EPAC1 but EPAC1-Mediated Rap1 activation does not account for PDE4 inhibitor-induced apoptosis. Blood 2004; 103:2661-2667 (PMID: 14615375).
Tiwari S, Dong H, Kim EJ, Weintraub L, Epstein PM and Lerner A. PDE4 inhibitors augment glucocorticoid-mediated apoptosis and signaling in B-CLL in the absence of exogenous adenylate cyclase stimulation. Biochem. Pharmacol. 2005: 69; 473-483 (PMID: 15652238).
Felekkis KN, Narsimhan RP, Castro AF, Quilliam LA and Lerner A. AND-34 activates phosphatidylinositol 3-kinase and induces antiestrogen resistance in a SH2 and GEF-like domain-dependent manner. Molecular Cancer Research. 2005: 3; 32-41 (PMID: 15671247).
Lerner A and Epstein P. Cyclic nucleotide phosphodiesterases as targets for treatment of haematological malignancies. Biochemical Journal. 2006: 393; 21-41 (PMCID: PMC1383661).
Everett P, Meyers JA, Makkinje A, Rabbi M and Lerner A. Curcumin augments vinca alkaloid and PDE4 inhibitor-induced apoptosis in B-CLL cells at clinically tolerable concentrations. Amer. J. Hematol. 2007: 82: 23-30 (PMID: 16947318).
Near RI, Zhang Y, Makkinje A, Vanden Borre P, and Lerner A. AND-34/BCAR3 differs from other NSP homologs in induction of anti-estrogen resistance, cyclin D1 promoter activation and altered breast cancer cell morphology. J. Cell. Physiol. 2007: 212: 655-665 (PMCID: PMC2640322).
Meyers JA, Taverna J, Chaves J, Makkinje A and Lerner A. PDE4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells. Clinical Cancer Research 2007: 13: 4920-4927 (PMCID: PMC2656255).
Garron ML, Arsenieva D, Zhong J, Bloom A, Lerner A, O’Neill GM and Arold ST. Structural insights into the association between BCAR3 and Cas family members; an atypical complex implicated in anti-oestrogen resistance. J. Mol. Biol., 2009: 386:190-203 (PMID: 19103205).
Rufanova VA, Alexanian A, Wakatsuki T, Lerner A and Sorokin A. Pyk2 mediates Rap1 activation by Endothelin-1 via p130Cas/BCAR3 cascade and regulates human glomerular mesangial cell adhesion and spreading. J. Cell. Physiol., 2009: 219:45-56 (PMID: 19086031).
Makkinje A, Near RI, Infusini G, Bloom A, Cai D, Vanden Borre P, Costello CE and Lerner A. AND-34 regulates late-phase, adhesion-dependent p130Cas serine phosphorylation and breast cancer cell growth pattern. Cellular Signaling 2009: 21:1423-35.
Near RI, Smith RS, Toselli PA, Freddo T, Bloom A, Vanden Borre P, Seldin D and Lerner A. AND-34/BCAR3 is required for structural integrity of the adult mouse lens. Molecular Vision 2009; 15:685-699.
Meyers JA, Su DW and Lerner A. CLL, B and T cells differ in their response to cyclic nucleotide phosphodiesterase inhibitors. J. Immunol. 2009: 182:5400-5411 (PMCID: PMC2676892)
Vanden Borre P, Near RI, Makkinje A, Mostoslavsky G and Lerner A. BCAR3/AND-34 can signal independent of complex formation with CAS family members or the presence of p130Cas. Cellular Signaling, 2011:23:1030-1040 (PMID:21262352)
Makkinje A, VandenBorre P, Near RI, Patel P and Lerner A. AND-34/BCAR3 augments the ability of p130Cas to bind the Src SH3 domain in a BCAR3-p130Cas complex-dependent manner. J. Biol. Chem. 2012: 287: 27703–27714.