Axl, a member of the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases, displays an increasingly important role in carcinogenesis. Analysis of 58 cutaneous melanoma lines indicated that Axl was expressed in 38% of them, with significant overrepresentation in NRAS- compared with BRAF-mutated tumors. Axl activation could be induced by autocrine production of its ligand, Gas6, in a significant fraction of Axl-positive tumors. Pearson's correlation analysis on expression data from five data sets of melanoma lines identified several transcripts correlating positively or negatively with Axl. By functionally grouping genes, those inversely correlated were involved in melanocyte development and pigmentation, whereas those positively correlated were involved in motility, invasion, and microenvironment interactions. Accordingly, Axl-positive melanomas did not express microphthalmia transcription factor (MITF) and melanocyte differentiation antigens (MDAs) such as MART-1 and gp100 and possessed a greater in vitro invasive potential compared with Axl-negative ones. Motility, invasivity, and ability to heal a wound or to migrate across an endothelial barrier were inhibited in vitro by Axl knockdown. Pharmacological inhibition of Axl using the selective inhibitor R428 had comparable effects in reducing migration and invasion. These results suggest that targeted inhibition of Axl signaling in the subset of melanomas lacking MITF and MDAs may represent a novel therapeutic strategy.

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Acute promyelocytic leukemia (APL;t M3 of the FAB 1 .1 classification) is a distinct, well-characterized clinical and morphological subtype of acute myeloid leukemia (AML) (1,2). It is cytogenetically distinguished by a reciprocal chromosome 15;17 translocation, which is present in 70-90% of cases and never seen in other AMLs or other types of malignancy (3, 4). Although the high frequency and specificity of the t(15;17), and the fact that it is often the only karyotypic aberration present (4), is strong evidence that it plays a crucial role in the pathogenesis ofAPL, the gene(s) directly involved in the chromosome 15 and 17 breakpoints have never been identified . We have previously shown that the APL chromosome 17 breakpoint lies between the c-erbB-2 and the retinoic acid receptor a (RARci) loci (5) . We report here the findings of RARct gene rearrangement and aberrant expression in APLs. Although acute promyelocytic leukemias (APLs) are consistently associated with a reciprocal chromosome 15;17 translocation, the gene(s) directly affected by the breakpoints have never been isolated. The chromosome 17 breakpoint maps to near the retinoic acid receptor a (RARa) locus. Investigation of20 APLs and a large series ofother neoplastic patients and normal controls revealed RARa gene rearrangements and aberrant transcripts only in the APL cases. These findings suggest that the RARce gene is involved in the APL chromosome 17 breakpoint, is implicated in leukemogenesis, and could be used as a marker for identifying leukemic promyelocytes. Materials and Methods Rearrangements and Aberrant Expression of theMolecular Studies. The K/S, IT, and P/R RARct cDNA probes were obtained by subcloning portions of the p63 plasmid (6) in 'Abbreviations used in this paper: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; BM, bone marrow ; RARa, retinoic acid receptor a.

The translocation t(8;16) (p11;p13) was found as the sole deviation from the normal karyotype in three patients with acute monocytic leukaemia. The bone marrow morphology was strikingly similar in the two cases where smears were available for re-evaluation: the leukaemic cells showed signs of differentiation, and active erythrophagocytosis was a particularly conspicuous feature. We suggest that t(8;16) (p11;p13) represents a new consistent abnormality in acute monocytic leukaemia, specifically associated with the differentiated subtype (M5b) and with pronounced phagocytic activity by the leukaemic monocytes.

Primary effusion lymphoma (PEL) harbors consistent infection by human herpesvirus-8, preferentially develops in immuno-