Document M4gGJRjx3Kkpmpjvyjxg35RVV

694 THE NEW ENGLAND JOURNAL OF MEDICINE - 19 percent of those in their 20s." This trend is likely to continue, since the proportion of women 30 to 34years old who were college graduates increased by 50 percent between 1975and 1987, and these women appear to be delaying marriage." Although the homogeneity of the patient population in the study by Berkowitz et al. lends itself to more accurate conclusions for a selected group of women, the data must be interpreted cautiously, particularly when one is considering other socioeconomic groups and more varied populations. Nevertheless, the message is clear and highly optimistic. What should be emphasized is the fact that the few pregnancy-related problems in nulliparous women who are 35 or older are readily manageable in 1990. Given sound genetic diagnosis and counseling, together with appropriate prenatal care and the judicious management of labor and delivery, the increasing number of women postponing first pregnancies can look forward to excellent outcomes. University of California, San Diego School of Medicine San Diego, CA 92103 ROBERT RESNIK,M.D. REFERENCES 1. Waters EG, Wager HP. Pregnancy and labor experiencesof elderly primigravidas. Am J Obstet Gynecol 1950; 59296-304. 2. National Center for Health Statistics, Ventura SJ. Trends and variations in first births to older women, 1970-86. Vital and health statistics. Series 21. No. 47. Hyattsville, Md.: Public Health Service, 1989. (DHHS publication no. (PHS) 89-1925.) 3. Berkowia GS, Skovron ML, Lapinski RH, Berkowia RL. Delayed childbearing and the outcome of pregnancy. N Engl J Med 1990; 322:659-64. 4. Resnik R . Pregnancy in women aged 35 years or older. In: Hollingsworth DR, Resnik R, eds. Medical counseling before pregnancy. New York: Churchill Livingstone, 1988:14-8. 5. Km DS, Dorchester W. Freeman RK. Advanced m a t e d age: the mature gravida. Am J Obstet Gynecol 1985; 152:7-12. 6. Spellacy WN, Miller SJ, Winegar A. Pregnancy after 40 years of age. Obstet Gynecol 1986; 68:4524. 7. Hook EB. Rates of chromosomal abnormalities at different maternal ages. Obstet Gynecol 1981; 58:282-5. 8. Stein ZA.A woman's age: childbearingand child rearing. Am J Epidcmiol 1985; 121:32742. 9. Menken J, Trussell J, Larsen U. Age and i n f d i t y . Science 1986 233: 1389-94. 10. Department of Commerce, Burtau of the Census. Educational attainment in the United States: Mamh 1987 and 1986. Current population reports. Series P-20. No. 428. Washington, D.C.: Government Printing Office, 1988. I 1. National Center for Health Statistics. Advance replt of Cnal marriage statistics, 1986. Monthly biostatisticsreport. Vol. 38. No.3. Suppl. 2. Hyans- ville. Md.: Public Heal~hService. 1989. CELLULAR ORIGINS OF HEMATOLOGIC NEOPLASMS THE entire hematopoietic system in all its complexity arises from a small number of stem cells that not only differentiate but also replenish the bone marrow by a process of self-renewal. These stem cells supply the marrow with committed progenitor cells that become the main hematopoietic cell types. Cells that move beyond the progenitor stage lose their capacity for self-renewal but retain the potential to differentiat, into erythrocytes, granulocytes, monocytes, megabr, yocytes, or lymphocytes. The idea that a stem cell or one of its immediate descendants is the source of hematopoietic neoplasms has ramifications for all types of cancer. A lesion that renders a stem cell neoplastic may explain how a tumor consisting mainly of mature differentiated cells can continue to grow. Moreover, the issue at hand -the cellular origins of hematologic neoplasms -has potentially broad therapeutic appli. cations: identifying the cell in which the transforming event begins could lead to treatment that would SW- cifically target the basic abnormality. The first and best evidence of a stem-cell defect in a cancer derives from work on chronic myelogenous leu. kemia. The presence of the Philadelphia chromosome (Ph'; due to a reciprocal translocation between chromosomes 9 and 22) in all cell lineages in the bone marrow of patients with chronic myelogenous leukeMia can only mean that the disease originates in a progenitor stem cell. The experiments of Fialkow et al.' with X-linked glucose-6-phosphate dehydrogen- ase isoenzymes support this conclusion. In female patients with chronic myelogenous leukemia who were heterozygous at the glucose-6-phosphate dehydrogenase locus, only one form of the enzyme was found in granulocytes, red cells, platelets, and macrophages. Thus, the root of the problem in chronic myelogenous leukemia lies in a precursor from which these diverse cells derive. More recent studies2 have shown that the translocation in the Ph' abnormality moves the c-& proto-oncogene from chromosome 9 to a position next to the bcr (breakpoint cluster region) gene on chromosome 22. The fused bcr-abl gene encodes a tyrosine kinase whose enzymatic activity is much greater than that of the normal tyrosine kinase product of c-abl. The importance of this genetic abnormality has been shown in the development of a disease strongly resembling chronic myelogenous leukemia in mice injected with syngeneic bone marrow cells carrying the fused bcr-ublgene (as a result of a retrovirus-mediated tech- 4 nique of gene transfer) (Rosenberg N: personal communication). With such compelling evidence that chronic myelogenous leukemia begins in a stem cell, it is still not clear why myeloid cells predominate in the chronic phase of the disease. Furthermore, the molecular basis for the progression of chronic myelogenous leukemia to a blast crisis remains a puzzle. When that progression occurs, the hematologic picture of orderly myeloid maturation shifts to an overwhelming proliferation of primitive myeloid, lymphoid, erythroid, megakaryocytic, or undifferentiated blasts. The bcr-ubl translocation is necessary for the develop ment of the disease's chronic phase, but the blast crisis may require additional genetic changes. The origin of a leukemic clone in an ancestral stem cell or committed progenitor cell implies that the pre- cursor can, up to a point, continue to differentiate .; f f.yol. 322 No. 10 *1/ EDITORIALS 695 ' rdless of its genetic lesion. This may explain the transcription as the cause," and away from a precur- nce of myeloid antigens on acute lymphoblastic sor common to both B cells and myeloid cells. yr - emia * =tibodies cells (detected with the use of monoclonal in the technique of imm~nophenotyping).~ The issue of localizing the cellular origin of multiple myeloma to either a hematopoietic stem cell or a . i t may also explain the presence of erythrocytic and primitive lymphocyte could be resolved by the identi- megakaryocytic antigens on leukemic cells from pa- fication of a specific genetic or chromosomal abnor- tients with acute myeloid leukemia.' In these cases, mality. Such chromosomal alterations are seen in hu- only a small percentage of cells have multilineage man follicular lymphomas and chronic lymphocytic markers, but there are also biphenotypic leukemias in leukemia, and they seem to arise in pre-B cells during which most of the cells express both lymphoid and an early step in the process of immunoglobulin-gene myeloid antigens. rearrangement.I3 Burkitt's lymphoma involves a These bizarre phenotypes can be compared with translocation of genes at a later stage of B-cell differ- the unusual rearrangements of immunoglobulin and entiation." A characteristic genetic marker has not T-cell-receptor genes that occur in acute lymphoblas- been identified in multiple myeloma, but there is tic leukemia. Normally, the stepwise rearrangements promise in recent work describing novel alterations in of these genes correlate with the stage of lymphocytic the c-my gene.'* It is uncertain whether the c-myc mu- differentiation. The process begins before the lymph- tations are relevant to the pathogenesis of myeloma or oid progenitor cell becomes committed to one lineage are an epiphenomenon. or the other, with rearrangements of both immuno- Oncogenetic defects that lead to hematologic neo- globulin and T-cell-receptor gene^.^,^ In hematopoiet- plasms can therefore occur at various points along the ic neoplasms with mixed phenotype^,^ inappropriate pathways taken by hematopoietic stem cells as they =arrangements have been found, such as immuno- differentiate into committed progenitor cells. The ge- globulin-gene rearrangement in malignant T cells and netic abnormality may become manifest in the pro- rearrangements of T-cell-receptor genes in malignant genitor cell itself or only after the altered precursor 3 cells. We can therefore infer that such cases origi- undergoes what appears to be normal differentiation. nate from a malignant lesion in an early progenitor of The new findings in multiple myeloma emphasize the the lymphoid line. complexity of self-renewal, gene expression, and cell Recent findings in multiple myeloma, usually con- differentiation in all neoplasms. Even so, it is now sidered to be a monoclonal proliferation of terminally possible to believe that by joining the resources of differentiated B cells, underline this point. Investiga- molecular and cell biology with astute clinical re- tions with antiidiotypic antibody markers,' i'mmuno- search it may be feasible to discover the cellular ori- chemistry, and flow c y t ~ m e t r yh~av, ~e shown that the gins of all cancers. From such knowledge will come an earliest identifiable precursor of the "myeloma cell" is entirely new foundation for the rational and specific an immature B cell with characteristics (plasma-cell treatment of cancer. antigen, cytoplasmic p chains, and immunoglobulingene rearrangements) identical to those of the mature malignant plasma cell. These aberrant pre-B cells New England Medical Center Boston, MA 021I 1 J.RACHEL BUCHSBAUM, M.D. ROBERT S. SCHWARTZ, M.D. have a high proliferative index and are thought to REFERENCES make up the self-renewing population in myeloma. A perplexing new finding complicates the story in I . Fialkow PJ, Jacobson RJ, PapayannopoulouT. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte. erythrocyte, myeloma. Both myeloid and plasma-cell antigens have been detected on fresh or cultured plasma cells from the bone marrow of patients with myeloma." platelet and monocyte/macrophage.Am J Med 1977;63:125-30. 2. Kuruock R. Gutterman JU,Talpaz M.The molecular genetics of Phila- delphia chromosomspositive leukemias. N Engl J Med 1988;319:990- 8. in this issue of the Journal, Epstein" and coworkers have taken the problem one step further with dualParameter flow cytometry. They identified malignant aneuploid plasma cells from patients with myeloma that expressed both myeloma-associated and non!Ymphoid markers. These results - as well as those the biphenotypic leukemias - may well reflect a transforming event in a multipotent stem cell. How- 3. Sobol RE,Mick R. Royston I, et al. Clinical importance of myeloidantigen expression in adult acute lymphoblastic leukemia. N Engl J Med 1987; 3161111-7. 4. Keininen M,Griffin JD, Bloomfield CD, Machnicki J, de la Chapelle A. Clonal ch~~mosomabl normalities showing multiplesell-lineage involvement in acute myeloid leukemia. N Engl J Med 1988;318:1153-8. 5. Greaves MF,Chan LC,Furley AJW, Waa SM,Molgaard HV. Lineage promiscuity in hematopoietic differentiation and leukemia. Blood 1986; 67:1-11. 6. Dyer MI.T-cell receptors/o rearrangements in lymphoid neoplasms.Blood 1989;74:1073-83. ever, the findings could also be due to the aberrant expression of normally quiescent lineage-specific gtnes by the malignant cells. The latter possibility ames because, after several passages in culture, myeloma cells may switch from the expression of one mon- 7. Kubagawa H,Vogler LB. Capra JD. et al. Studies on the clonal origin of multiple myeloma. J Exp Med 1979; 1W792-807. 8. Grogan TM, Dune BGM, Lomen C, et al. Delineation of a novel pre-B cell component in plasma cell myeloma:immunochemical,immunophenotypic, genotypic, cytologic, cell culture, and kinetic features. Blood 1987;7093242. 9. Epsain J, Barlogie B, KatunannJ , Aleranian R. Phenotypic heterogeneity q t i c antigen to the expression of a number of myeloid antigens." This kind of in vitro modulation of phenotype points to the defective regulation of gene in aneuploid multiple myeloma indicates pre-B cell involvement. Blood 1988;71:861-5. 10. Gmgan TM.Dune BGM, Spier CM.Richter L, Vela E. Myelomonocytic antigen positive multiple myeloma. Blood 1989; 73:763-9.