Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer. Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination, we have measured telomere length, telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5. In all mortal populations, telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures. When transformed cells reached crisis, the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed. In immortal cells, telomere length and frequency of dicentric chromosomes stabilized after crisis. Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations. These results suggest that chromosomes with short (TTAGGG)n tracts are recombinogenic, critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization.

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1992.tb05245.x

Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.

Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)

Folate deficiency causes massive incorporation of uracil into human DNA (4 million per cell) and chromosome breaks. The likely mechanism is the deficient methylation of dUMP to dTMP and subsequent incorporation of uracil into DNA by DNA polymerase. During repair of uracil in DNA, transient nicks are formed; two opposing nicks could lead to chromosome breaks. Both high DNA uracil levels and elevated micronucleus frequency (a measure of chromosome breaks) are reversed by folate administration. A significant proportion of the U.S. population has low folate levels, in the range associated with elevated uracil misincorporation and chromosome breaks. Such breaks could contribute to the increased risk of cancer and cognitive defects associated with folate deficiency in humans.

https://www.pnas.org/content/pnas/94/7/3290.full.pdf

Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage

BIOCHEMISTRY IN ANAESTHESIA Modern Trends In Anaesthesia. II. Aspects of Hydrogen lon Regulation and Biochemistry in Anaesthesia. Edited by Prankis T. Evans, M.B., B.S., F.R.C.S., F.F.A. R.C.S., and T. Cecil Gray, M.D., FF.A. R.C.S., Hon.F.F.A. R.A.C.S. (Pp. 219+vii; illustrated. 60s.) London: Butterworths. 1962. In this stimulating book a group of experts have written on hydrogen-ion regulation and biochemistry in anaesthesia. This vast subject has been divided rather artificially and only certain aspects of biochemistry have been covered, and the divisions are more related to clinical practice than basic physiology and biochemistry. TIhe sections have been written by specialists in each field; the material they contain is beyond criticism, and there is valuable practical advice. Some chapters are well written, though others are not so easy to read. All are packed with information, and, what is equally valuable, they provide a source of further information for the inquiring mind, for the references and bibliographies are excellent. It is a pleasure to have complicated electrophysics presented in a readable way (\" Measurement of pH and Pco l\"); \"The Cholinesterases\" is an embracing account of difficult physiological and biochemical problems. Throughout the book there is a wealth of valuable material, indeed so much so that at times too much appears to have been attempted within the space available, as in \" Effects of Hypercapnia.\" These are minor criticisms of a good book, or perhaps it would be wiser to call it a collection of papers on chosen subjects, for there is understandably a lack of cohesion among the various chapters, and even some slight overlapping, which renders the whole less valuable than its several parts. No one can read these papers without interest and profit (and occasionally amusement) and they should fulfil the editor's hope that they will stimulate further interest in basic science. The book is well presented; the printing and paper are good, but the price will not encourage widespread use of the book among the younger members of our specialty. G. E. H. ENDEPBY.

Blood Groups in Man.

Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage.

The Philadelphia chromosome (Ph′) is found in the blood cells of about 90% of patients with chronic myeloid leukaemia (CML) and usually results from the reciprocal chromosome translocation t(9; 22)1,2. This translocation relocates the proto-oncogene c-abl, normally found on chromosome 9q34, to within the breakpoint cluster region (bcr) on chromosome 22qll (refs 3–8). The juxtaposition of c-abl and the 5′ portion of bcr appears to be the critical genomic event in CML and results in a novel 8-kilobase (kb) fused abl/bcr transcript9,10 and a c-abl-related protein of relative molecular mass 210,000 (ref. 11). About 10% of adult patients diagnosed as CML lack the Ph′ chromosome; they represent a heterogeneous group of disorders which are difficult to diagnose precisely12. We have examined five patients with CML whose leukaemic cells have a normal karyotype. We report here that two of the patients showed the same genomic change as occurs in Ph′-positive CML, but the change resulted from a mechanism other than chromosomal translocation. The remaining three patients showed no genomic rearrangement. This genomic diversity correlated with the clinical differences between the patients.

Genomic diversity correlates with clinical variation in Ph'-negative chronic myeloid leukaemia.

Lambo, T. A. (1956). Brit. med. J., 2, 1388. (1960). Ibid., 2, 1696. Laubscher, B. J. F. (1951). Sex, Custom, and Psychopathology. Routledge and Kegan Paul, London. McGeorge, J. (1942). Med. J. Aust., 1, 67. Mahi, Tigani El (1959). Africa: Social Change and Mental Health. W.H.O. Odegard, 0. (1932). Acta physiol. scand., Suppl. 4, p. 11. Read, C. S. (1936). Brit. med. J., 1, 631. Sainsbury, P. (1955). Suicide in London. Chapman, London. Stengel, E. (1950). Recent Progr. Psychiat., 2, 691. and Cook, N. G. (1954). J. forens. Med., 1, No. 5. Tooth, G. (1950). Studies in Mental Illness in the Gold Coast. Colonial Research Publ. No. 6. H.M.S.O., London. Wicksell, S. (1934). Svenska Forenigrens for Psykisk Halsovard Smaskrifter, No. 7. Quoted by Dahlgren (1945). Yap, P. M. (1958). J. ment. Sci., 104, 266.

https://www.bmj.com/content/bmj/2/5312/1097.full.pdf

An abnormal chromosome in chronic lymphocytic leukaemia.

In PHA-cultured lymphocytes, about 8% of metaphases from 32 women were aneuploid compared to 4% of metaphases from 35 men A significant part of this aneuploidy was characterized by sex chromosome involvement: in women, the loss or gain of X chromosomes; in men, the gain of X chromosomes and the loss or gain of Y chromosomes The incidence of this aneuploidy was positively age-related for both sexes Premature division of the X-chromosome centromere was closely associated with X-chromosome aneuploidy in women and men, and appeared to be the mechanism of nondisjunction causing this aneuploidy Premature centromere division (PCD) indicated a dysfunction of the X-chromosome centromere with aging, and this dysfunction was the basic cause of age-related aneuploidy A similar mechanism of nondisjunction may operate for the Y chromosome of men, but could not be clearly demonstrated because of the low incidence of Y-chromosome aneuploidy

Total aneuploidy and age-related sex chromosome aneuploidy in cultured lymphocytes of normal men and women

Cytogenetic and Cytochemical Studies on Marrow Cells in B12 and Folate Deficiency

About 20% of leukemic bone marrow cells from each of two patients with B-cell lymphoid leukemias showed apparent translocations which appeared to be the result of telomeric association. In one patient, whole chromosomes were associated telomere to telomere in pairs; in the other patient, telomeres of whole chromosomes were associated with breakpoints located close to the proximal or distal ends of the heterochromatic band 1q12. Repeated base sequences, particularly (CA)n sequences, are believed to be the basis of telomere pairing, and likewise repeated base sequences of heterochromatin may explain the association of 1qh and telomeres. Telomeric association may be considered as a potential origin of new stable cytogenetic combinations that have a role in oncogene transposition and tumor etiology.

https://link.springer.com/content/pdf/10.1007/BF00291396.pdf

Peter H. Fitzgerald

Papers

Genomic diversity correlates with clinical variation in Ph'-negative chronic myeloid leukaemia.

An abnormal chromosome in chronic lymphocytic leukaemia.

Total aneuploidy and age-related sex chromosome aneuploidy in cultured lymphocytes of normal men and women

Cytogenetic and Cytochemical Studies on Marrow Cells in B12 and Folate Deficiency

Telomeric association of chromosomes in B-cell lymphoid leukemia.