The ordered rearrangement of immunoglobulin (Ig) component genes promote differentiation and also serve as molecular "markers" of specific stages during B-cell development. We and colleagues have shown that Recombinase Activating Gene (RAG) deficient and JH deficient mice alone or bearing Ig transgenes have defined, developmentally arrested pro-B cell (all Ig genes germline), pre-B cell (heavy chain Ig genes rearranged, light chain genes germline), or immature B cell (heavy and light chain genes rearranged) bone marrow B-lymphoid populations. Phenotypic and functional analysis of the B-lymphocytes and pre-B cells arising in these genetically manipulated "knock-out" mice show that these animals present a unique in-vivo system with which to study B-cell development.

Our lab uses genetic engineering ("knock-out" and "knock-in") technology to create mice suited for the detailed study of normal and abnormal B-lymphocyte development. One series of experiments builds on the observation that certain B-lymphoid Acute Lymphoblastic Leukemias (B-ALL) may represent B-lineage precursors that are transformed at very specific stages of differentiation.

In humans, E2A-PBX1 and p190 BCR-ABL appear to preferentially transform pre-B and pro-B-lymphocytes respectively. We are therefore using E2A-PBX1 and p190 BCR-ABL leukemogenic fusion proteins engineered to provide constitutive or inducible expression in the RAG-deficient or JH-deficient murine models described above. These new murine models allow us to study, in-vivo, abnormal lymphocyte development in the context of genetically identical, developmentally arrested bone marrow populations.

Young FM, Pinkert CA, Bottaro A. Analysis of Lymphocyte Development and Function Using the RAG-Deficient Blastocyst Complementation System. Methods Mol Biol. 271:77-90, 2004.

Anolik J, Looney RJ, Bottaro A, Sanz I, Young F. Down-regulation of CD20 on B cells upon CD40 activation. Eur J Immunol. 33:2398-409, 2003.

Anolik JH, Campbell D, Felgar RE, Young F, Sanz I, Rosenblatt J, Looney RJ. The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 48:455-459, 2003.

Xing L, Bushnell TP, Carlson L, Tai Z, Tondravi M, Siebenlist U, Young F, Boyce BF. NF-kappaB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis. J Bone Miner Res. 17:1200-10, 2002.

Malynn BA, Shaw AC, Young F, Stewart V, Alt FW. Truncated immunoglobulin Dmu causes incomplete developmental progression of RAG-deficient pro-B cells. Mol Immunol. 38:547-56, 2002.

Kuzin II, Snyder JE, Ugine GD, Wu D, Lee S, Bushnell T Jr, Insel RA, Young FM, Bottaro A. Tetracyclines inhibit activated B cell function. Int Immunol. 13:921-31, 2001.

Khorana AA, Rosenblatt JD, Young FM. Immunopathogenesis of HIV and HTLV-1 infection: mechanisms for lymphomagenesis. Cancer Treat Res 104:19-74, 2001.

Kuzin II, Ugine GD, Wu D, Young F, Chen J, Bottaro A. Normal isotype switching in B cells lacking the I mu exon splice donor site: evidence for multiple I mu-like germline transcripts. J Immunol. 164:1451-7, 2000.

Bottaro A, Young F, Chen J, Serwe M, Sablitzky F, Alt FW. Deletion of the immunoglobulin intronic enhancer and associated matrix attachment regions decreases, but does not abolish class switching at the mu locus. Int Immunol 10:799-806, 1998.

Young F, Mizoguchi E, Bhan AK, Alt FW. Constitutive Bcl-2 expression during immunoglobulin heavy chain-promoted B cell differentiation expands novel precursor B cells. Immunity 6:23-33,1997.