Progenitor B-1 B-cell acute lymphoblastic leukemia is associated with collaborative mutations in 3 critical pathways.

B-1 and B-2 lymphocytes are derived from distinct developmental pathways and represent layered arms of the innate and adaptive immune systems, respectively. In contrast to a majority of murine B-cell malignancies, which stain positive with the B220 antibody, we discovered a novel form of B-cell leukemia in NUP98-PHF23 (NP23) transgenic mice. The immunophenotype (Lin- B220- CD19+ AA4.1+) was identical to that of progenitor (pro) B-1 cells, and VH gene usage was skewed toward 3' V regions, similar to murine fetal liver B cells. Moreover, the gene expression profile of these leukemias was most similar to that of fetal liver pro-B fraction BC, a known source of B-1 B cells, further supporting a pro-B-1 origin of these leukemias. The NP23 pro-B-1 acute lymphoblastic leukemias (ALLs) acquired spontaneous mutations in both Bcor and Janus kinase (Jak) pathway (Jak1/2/3 and Stat5a) genes, supporting a hypothesis that mutations in 3 critical pathways (stem-cell self-renewal, B-cell differentiation, and cytokine signaling) collaborate to induce B-cell precursor (BCP) ALL. Finally, the thymic stromal lymphopoietin (Tslp) cytokine is required for murine B-1 development, and chromosomal rearrangements resulting in overexpression of the TSLP receptor (CRLF2) are present in some patients with high-risk BCP-ALL (referred to as CRLF2r ALL). Gene expression profiles of NP23 pro-B-1 ALL were more similar to that of CRLF2r ALL than non-CRLF2r ALL, and analysis of VH gene usage from patients with CRLF2r ALL demonstrated preferential usage of VH regions used by human B-1 B cells, leading to the suggestion that this subset of patients with BCP-ALL has a malignancy of B-1, rather than B-2, B-cell origin.

Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma.

Treatment of patients with human immunodeficiency virus (HIV) protease inhibitors such as ritonavir can result in increases in CD4(+) T-cell counts that are independent of a reduction in HIV-1 viral load. This lack of correlation between the 2 has led to the identification of additional effects of ritonavir that potentially alter HIV disease pathogenesis. Our previous studies indicated that ritonavir directly affects immune cell activation, proliferation, and susceptibility to apoptosis. We show here that ritonavir inhibited the activation and proliferation of primary endothelial cells and decreased the production of tumor necrosis factor alpha (TNF-alpha) interleukin 6 (IL-6), IL-8, and vascular endothelial growth factor, factors that all contribute to tumor neovascularization and to the development of Kaposi sarcoma (KS) lesions. Ritonavir also suppressed the expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin, which correlated with a functional decrease in leukocyte adhesion. Transcriptional activation of nuclear factor-kappaB, as induced by the KS-promoting factor TNF-alpha, the HIV-1 Tat protein, or the human herpesvirus 8 protein ORF74, was inhibited by ritonavir. KS-derived cell lines underwent apoptosis in vitro after treatment with ritonavir at concentrations that are obtained in clinical therapy (3-15 microM). In a KS mouse xenotransplantation model, ritonavir inhibited tumor formation and progression by KS-derived cells. Taken together, these data suggest that ritonavir has antineoplastic effects that are independent from its ability to inhibit the HIV protease.