Survivals of two series of CLL patients (99 from a retrospective series and 196 from a prospective series) were studied separately. The three main staging systems (Rai, Binet, Rundles) agreed well, but as far as survival is concerned, too many stages are defined. The authors performed a Cox multivariate analysis of survival in order to isolate important prognostic factors at diagnosis and to use them to build a simple three-stage classification. Thrombopenia and anemia appeared as the most important risk factors. Among the nonanemic and nonthrombopenic patients, the number of involved areas was clearly related to prognosis in the authors' two series. This study allowed the authors to propose a new classification in three prognostic groups. Group C: anemia (Hb less than 10 g) and/or thrombopenia (platelets less than 100,000/mm3); about 15% of the patients; median of 2 years. Group B: no anemia, no thrombopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver); about 30% of patients; median of 7 years. Group A: no anemia, no thrombopenia, less than three involved areas; about 55% of patients; the survival of this group does not seem different from that of the French population of the same age and sex distribution. This three-stage classification only requires clinical examination and routine hemogram, has a good prognostic value which was confirmed on the series of Montserrat and Rozman (146 patients), and should therefore be helpful in planning new clinical trials.

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Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.

The gene encoding the ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia. The consequence of these mutations on the onset of the disease remains obscure. Here, we show that RPS19 plays an essential role in biogenesis of the 40S small ribosomal subunit in human cells. Knockdown of RPS19 expression by siRNAs impairs 18S rRNA synthesis and formation of 40S subunits and induces apoptosis in HeLa cells. Pre-rRNA processing is altered, which leads to an arrest in the maturation of precursors to the 18S rRNA. Under these conditions, pre-40S particles are not exported to the cytoplasm and accumulate in the nucleoplasm of the cells in perinuclear dots. Consistently, we find that ribosome biogenesis and nucleolar organization is altered in skin fibroblasts from DBA patients bearing mutations in the RPS19 gene. In addition, maturation of the 18S rRNA is also perturbed in cells from a patient bearing no RPS19-related mutation. These results support the hypothesis that DBA is directly related to a defect in ribosome biogenesis and indicate that yet to be discovered DBArelated genes may be involved in the synthesis of the ribosomal subunits. IntroductionDiamond-Blackfan anemia (DBA) is a rare pure red blood cell aplasia of childhood characterized by the absence or decreased numbers of erythroid precursors in the bone marrow but an otherwise normal cellularity. Approximately 40% of the DBA patients present various somatic malformations that mostly occur in the cephalic area but also in the hand and/or limb, urogenital tract, and heart. [1][2][3] Clinical expression in DBA is highly heterogeneous, and evolution of the disease is unpredictable. Treatment includes steroid therapy and transfusion with iron chelation. Bone marrow or cord blood transplantation is the only curative treatment but requires an HLA-matched sibling and is mostly reserved to patients with severe complications.It has been established that 25% of the DBA patients bear a mutated allele of the gene encoding the ribosomal protein S19 (RPS19). [4][5][6] RPS19 is one of the 32 proteins that assemble with the 18S ribosomal RNA (rRNA) to form the small (40S) ribosomal subunit. RPS19 is an essential protein, as homozygous deletion of RPS19 in the mouse leads to embryonic lethality before implantation at the blastocyst stage. 7 A wide range of mutations have been identified in DBA patients, from missense to nonsense mutations and from partial to complete deletion of one allele. 3,5,6 Some missense mutations affect both the stability and the intracellular transport of RPS19. 8 Consistent with a role in DBA pathogenesis, depletion of RPS19 with specific siRNAs severely alters proliferation and differentiation of erythroleukemic cell lines or CD34 ϩ cells in culture. [9][10][11] Although DBA is to date the only genetic disease linked to mutation of an autosomal ribosomal protein gene, a number of other bone marrow failure symptoms (dyskeratosis congenita, cartilagehair hypoplasia, and Shwachman-Diamond ...