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VOL 19, NO 1 FEBRUARY 1992 Semi0nars 0 in - - -IF-? : ' ,', - \- I., EDITOR-IN-CHIEF JohnW. Yarbro, MD, PhD ASSOCIATE EDITORS Richard S. Bornstein, MD Michael J. Mastrangelo, MD Myelodysplastic Syndromes 011, MD, anh Alan F. List, MD, Guest Editors .List Jean E. Goasguen Jacobs Peter C. Nowell G. Levine Clara D. Bloomfield hiro Kizaki H. Phillip Koeffler VOL 19, NO 1 Seminars in Oncology Myelodysplastic Syndromes FEBRUARY 1992 Table of Contents Myelodysplastic Syndromes:Introduction ..................................... Donald C. Doll and Alan F. List Classification and Morphologic Features of the Myelodysplastic Syndromes....Jean E. Goasguen and John M.Bennett Biology and Pathogenesis of the Myelodysplastic Syndromes.........Alan F. List and Allan Jacobs Chromosome Abnormalities in Myelodysplastic Syndromes................................... Peter C. Nowell 1 4 14 25 In Vitro Marrow Culture Studies in the Myelodysplastic Syndromes................Peter L. Greenberg 34 Leukemias and Myelodysplastic Syndromes Secondary to Drug, Radiation, and Environmental Exposure.......................................................................... Ellis G. Levine and Clara D. Bloomfield 47 Chemotherapy and Bone Marrow Transplantation for Myelodysplastic Syndromes Bruce D. Cheson 85 Differentiation-Inducing Agents in the Treatment of Myelodysplastic Syndromes Masahiro Kizaki and H. Phillip Koefler 95 Treatment of Myelodysplastic SyndromesWith Hemopoietic Growth Factors Peter L. Greenberg 106 Biology and Pathogenesis of the Myelodysplastic Syndromes Alan F. List and Allan Jacobs 0UR KNOWLEDGE of the pathogenesis of the preleukemic states has evolved times that for acute myeloid leukemia. Among persons over 60 years of age, the incidence was considerably since the French-American-Brit- as high as 0.75 per 1,000 per year. Among a ish (FAB) Group characterization of the myelo- group of patients over 55 years undergoing dysplastic syndromes into distinct morphologi- hematologic screening, the incidence of previ- cal subgroups. It is now clear that the ously undiagnosed cases of MDS was 1.5 for hematologic manifestations that call attention every 1,000individuals screened. to these disorders represent a late event in the In the majority of patients, there is no family transformation of hematopoietic stem cells, in history or identifiable genetic predisposition to which a single genetically altered clone domi- the development of hematologic malignancy. nates blood cell production. Prchal et al,*using Although MDS is rare in persons less than 50 glucose-6-phosphate dehydrogenase (G6PD) years of age, the incidence of familial cases is polymorphism in heterozygousfemales and cyto- highest among persons in this age group. Among genetic markers, first demonstrated that these 550 adults with de novo MDS evaluated by disorders may arise in a primitive hematopoietic Fenaux et a18 over a 10-year period, patients stem cell common to both myeloid and lym- under 50 years of age accounted for less than phoid progenitors. Subsequent studies of DNA 7% of cases. Familial cases of myelodysplasia, polymorphisms at X-linked and cytoge- however, represented 14% of patients in the netic analyses of bone marrow progenitor~~~' younger cohort, a frequency 35 times that in the have confirmed that these disorders result from older age group. The distribution of FAB types clonal expansion of a multipotent or pluripotent and karyotypic abnormalities differed signifi- hematopoietic progenitor. cantly between the groups. Both refractory Current estimates of the incidence of the anemia with excess of blasts in transformation myelodysplastic syndromes (MDS) remain im- (RAEB-t) (35% v 9%) and structural or numer- precise. Because of the relatively recent adop- ical deletions of chromosome 7 (44% v 4%) tion of the FAB terminology, the Surveillance, were more frequent among patients under 50 Epidemiology, and End Results (SEER) pro- years of age. This pattern is analogous to that in gram of the National Cancer Institute has not the pediatric population with myelodysplasia. captured specific data regarding the prevalence Though rare in children, two disorders, juvenile of these disorders. A Leukemia Research Foundation epidemiologic study in 1984 estimated chronic myeloid leukemia (JCML) and the monosomy-7 syndrome, account almost entirely the incidence of MDS to be approximately 75% for the types of myelodysplasia seen in pediatric that of acute myeloid leukemia (AML).7 Because MDS is primarily a disease of the elderly, institutions caring for older populations have reported a much higher incidence rate. At the Royal Victoria Hospital in Bournemouth, UK, Hamblin and Oscier7 reported an incidence six patients. There is considerable overlap in the hematologic manifestations of these disorders, which include hepatosplenomegaly, leukocytosis, anemia, thrombocytopenia, excess marrow blasts, and a high frequency of conversion to acute leukemia. Juvenile chronic myeloid leuke- mia is the pediatric equivalent of chronic my- From the Section of HematologylOncologv and Bone Marrow Transplantation Program, Department of Internal Medicine, Universiw of Arizona College of Medicine, Tucson, and Department of Hematologv, Universiv of Wales College of elomonocytic leukemia (CMML), whereas the monosomy-7 syndrome displays a clear familial tendency?-'5The congenital chromosome fragility states, such as Fanconi's anemia and other Medicine, Heath Park, Cardiff; Wales. Address reprint requests to Alan F. List, MD, Arizona Cancer Center,Room 3947, Universiy of Arizona, Tucson,AZ 85724. Copyright 0 1992by W.B. Saunders Company 0093-775419211901-0004$05.00l0 related syndromes, are associated with intrinsic stem cell dysfunction and an increased incidence of MDS and acute leukemia, but account for only a minority of childhood MDS cases.'h-'x Other hematologic disorders associated with 14 Seminars in Oncology, Vol 19, No 1 (February), 1992: pp 14-24 BIOLOGY AND PATHOGENESIS 15 disturbed stem cell development have been increasingly recognized to predispose to the development of hematologic malignancy, and in particular, the myelodysplastic syndromes. The best characterized are paroxymal nocturnal hemoglobinuria (PNH) and aplastic anemia. The high rate of autologous bone marrow recovery with the use of antilymphocyte globulin (ALG) preparations has altered the natural history of aplastic anemia considerably. Unlike patients undergoing allogeneic bone marrow transplantation, hematologic recovery is generally incomplete with immunosuppressive therapy, implying persistence of an intrinsic stem cell defect. Of 38 patients with severe aplastic anemia survivingmore than 2 years after treatment with ALG, Tichelli et aii9 reported emergence of cytogenetically confirmed refractory anemia in five patients (13%), a median interval of 48 months after diagnosis. DePlanque et alZ0similarly noted development of MDS in 8 of 60 (13%) 2-year survivors after ALG, and in 4 patients this preceded development of acute myeloid leukemia. The probability that MDS would develop as a late complication increased with duration of follow-up reaching a frequency of 26% at 7 years' observation. GENOTOXIC AGENTS The nonrandom pattern of cytogenetic dele- tions affectingchromosomes 5 and 7 that charac- terize the myelodysplastic syndromes corre- spond to those identified in patients with therapy-related and leukemias aris- ing in patients occupationally exposed to chemi- ,g cal mutagens.M26lndeed occupational or thera- peutic exposure to a variety of potentially genotoxiccompounds known to induce stem cell injury is associated with an increased incidence of both MDS and AML. The risk of developing either of these hematologic malignancies in workers exposed to benzene has been shown to rise proportionately with cumulative expo- whereas low levels of ionizing radiation appear more leukemogenic than high-dose, ther- apeutic irradiati~n.~'"~ The leukemogenic risks associated with expo- sure to anticancer therapy are by far the best characterized. Data accumulated from popula- tion-based studies of patients with Hodgkin's disease, non-Hodgkin's lymphoma, ovarian can- cer, gastrointestinal malignancy, and polycythemia vera have demonstrated a complex relationship between exposure to the offending agent and risk of developing a metachronous myeloid ~nalignancy.~'"A~n excess risk of treatmentrelated MDS or AML becomes apparent immediately following completion of cytotoxic therapy and reaches its peak nearly 5 years after initiation of treatment, with an excess risk persisting up to 10 years. The cumulative risk is greatest for patients treated with chemotherapy, and alkylating agents in particular, but is proportionate to the dose and duration of alkylator therapy.32,33,36T3r8eatment with radiotherapy alone is associated with a modest but measurable risk of hemopoietic neoplasia, but does not compound the risk attributed to chemotherapy alone in Hodgkin's patients receiving combined modality therapy.32,4c*A4s1in de novo MDS, age remains a consistent variable affecting susceptibility to development of treatment-related myeloid n e ~ p l a s i a . " . ~Th~e. r~is.k~ ~ ~ ~ is greatest for patients over 40 years of age with relapsed disease, and for patients receiving prolonged treatment with chemotherapy. Leukemias that develop following cytotoxic therapy are invariably preceded by a myelodysplastic phase and are generally accompanied by cytologic evidence of trilineage d y ~ p l a s i a .M~a~les predominate in both de novo and secondary forms of MDS. The reasons for this apparent sexual disparity are not clear; however, exposure differences and the known hemopoietic stimulatory effects of androgens may account for the seeming sexual disparity in MDS prevalence. Though exposure to genotoxic agents clearly increases the risk of MDS, a history of such exposure can be elicited from only a minority of patients. Among 68 patients with MDS evaluated at the Arizona Lancer Center between Blu,- 3 1 3 7o ) had received p r i T treatment with chekotherapy, and 5 t m t i ~ e . ~ ~ ~ haa a history of radiation or benzene exposure. Whether exposure to unrecognized environmental toxins contributes to the development of MDS in the remaining patients is not clear. In a prospective case-control study performed at the University Hospital of Wales, a higher frequency and intensity of exposure to petrochemicals and other potential chemical mutagens was 16 LIST AND JACOBS observed in personswith de novo MDS (P < 0.01): permanent and appears limited to agents such A second study by Goldberg et ar7did not show a as ionizing radiation and alkylating agents, and higher frequency of genotoxin exposure. How- is not observed with repeated exposure to cycle- ever, patients with occupational exposure to specific agents such as the antimetabolites. In benzene were excluded, and there was an unex- large animals with compromised stem cell re- pectedly high exposure rate in the control group. serve following high doses of a bifunctional Among patients with acute myeloid leukemia, alkylator, hematopoiesis is maintained by a Crane and K e a t i ~ ~nogte~d~a greater frequency succession of individual stem cell clones which of exposure to genotoxins in patients with an persists for the lifetime of the animal. M-hh A antecedent preleukemic phase. Tobacco smoke, similar pattern of clonal succession is demonstra- which contains a number of potential leuke- ble in hone marrow allograft recipients by mogens, including nitrosamines, benzene, and analysis of restriction-fragment-length polymor- radioactive compounds (polonium-210), has not p h i s m ~ . ~ ~ been specificallyaddressed as a potential patho- Clonal hematopoiesis per se does not neces- genetic factor in myelodysplasia. Case-control sarily imply a predisposition to malignancy and studies have demonstrated a positive associa- requires cautious interpretation. Nevertheless, tion between cigarette smokingand the develop- in persons with compromised hematopoietic ment of acute myeloid leukemia in adults, reserve, sustained clonal hematopoiesis may be suggesting a similar relationship may also exist a requisite event for initiation of neoplasia. In .for MDS.49-53 patients with aplastic anemia, for example, who have a rrcognized excess risk of MDS, patterns SENESCENCE AND CLONAL SELECTION of X-chi-omosome inactivation in peripheral The clear age dependence for development blood and marrow have shown clonal hematopoi- of both de novo and secondary MDS implies esis in up to 50% of patients.68.6I9nvestigators at factors inherent to hematopoietic senescence as the Univxsity Hospital of Wales have examined well as spontaneous and/or chemical-induced clonality of hematopoiesis among hematologi- genetic insults represent important pathoge- cally normal individuals in complete remission netic features. Evidence from murine as well as following conventional chemotherapy for malig- human studies has shown an age-related decline nant lymphoma for a minimum of 1 year.'." in stem cell reserve and proliferative capac- Interestingly, monoclonal hematopoiesis was ity.54-5T8hese changes are accompanied by de- demonstrable in up to 57% of female subjects creased recovery of erythroid p r o g e n i t o r ~ , 5 ~ . ~ ~u~s'ing an X-linked probe. Conversely, 3 of 18 due in part to defective local priming by the (17%) normals, each of whom were over 70 micr~-environment.~'T-~h~e relation between years of age, had evidence of clonal restriction, these age-related changes in hematopoiesis and suggesting an associationbetween age and clonal development of MDS remain speculative, how- hematopoiesis. These patients will be followed ever such changes may favor selective out- prospectively to assess their risk for secondary growth of individual clones with a proliferative myeloid neoplasia. Nonetheless, these data pro- advantage. vide preliminary evidence that clonal restric- Perhaps the best model in which to assess tion, whether due to age or toxin exposure, these changes and the relation to malignant represents an early event in susceptibility to transformation is in populations with a defined MDS. risk of MDS, as in the setting of exposure to recognized leukemogens. It is clear from animal MOLECULAR EVENTS models and clinical observations that the latent Identification of nonrandom karyotypic abnor- interval between exposure to an offending geno- malities in the myelodysplastic syndromes con- toxin agent and clinical detection of MDS may firmed the clonality of these disorders and their extend over several years. Animal studies have relation to specific clinical and biological fea- shown that stem cell self-renewal capacity is tures." Mounting evidence indicates that acqui- compromised proportionate to the degree of sition of chromosome aberrations represents a toxic i n s ~ l t .T~h~is. l~os~s in stem cell reserve is relatively late event in the pathogenesis of BIOLOGY AND PATHOGENESIS MDS. Indeed, clonal cytogenetic abnormalities are lacking in up to 50% of patients at initial diagnosis and may be acquired during the course of hematologic progression. This has led to the proposal that at least two steps are involved in the pathogenesis of MDS: an early step that leads to expansion of a genetically unstable stem cell clone, followed by acquisition of a chromosome abnormality, which may confer some selective growth a d ~ a n t a g e . ~ ~ . ~ ~ Studies of experimental neoplasia indicate that early events may result from genetic rnutations that alter cell growth.'' Mutations affecting the regulatory domains of rus protooncogenes in particular have been associated with mutagen-induced neoplasia in animal systems and have been extensively evaluated in MDS. Rus gene products are guanine-nucleotide-binding proteins that couple membrane receptors to phospholipase-C.76 The growthpromoting effect of these oncoproteins derives in part from their ability to augment protein kinase-C activati~n.""S~elective hybridization studies using synthetic oligo-deoxynucleotide probes specific for activating mutations of each of the three rus gene alleles have demonstrated mutations predominantly affecting N-rus in 30% to 40% of patients with MDS.79-8M1 utant ras alleles are detected in all FAB subtypes but are found with greatest frequency in CMML. Among 75 patients evaluated by Jacobs and associates (Table l), 21 of 31 patients with CMML (68%) had mutant rus alleles compared to a prevalence of 36% among 44 patients with other FAB types. The frequency of leukemic conversion was significantly higher in patients harboring mutant rus alleles (14 of 39 [36%] v 2 of 36 [5.5%]). Table 1. Ras Mutations in Patients With Myelodysplastic Syndrome Refractow anemia (RA) RA with ringed sideroblasts (RARSI RAEB/RAEB-t CMML Ras Mutations No. N K H Total ~~ 18 3 3 - 6 1631 10 2 - 31 11 6 3 1 4 7 3 21 Total 75 19 10 8 37 NOTE. Fromthe University of Wales PreleukerniaUnit. Adapted with premission.= 17 The prevalence of mutations affecting regula- tory domains of the C-FMS proto-oncogene has also been investigated. The C-FMS gene en- codes the receptor for macrophage-colony stim- ulating factor (M-CSF) and possesses ligand- dependent tyrosine kinase acti~ity."~M" utations in codons 969 and 301 produce unrestricted tyrosine kinase and increase in vitro transformation The gene encod- ing FMS is located on the long arm of chromo- s o m e 5 q 3 3 . 3 ) in the region commonly deleted in hematologic malignancies.88The C a r d i E r m p ifetected FMS mutations in 9 (13%) of 67 patients with MDS and 5 (10%) of 48 patients with acute myeloid leukemia.89Mutations at codon 969 predominate and are detected prima- rily in patients with chronic myelomonocytic leukemia (6 of 30 patients; 20%) and my- elomonocytic variants of acute leukemia. Tobal et aIw found a similar distribution in patients with MDS, suggesting that FMS mutations may play a role in monocytic lineage commitment. Although ius mutations may be acquired at any stage of MDS e v ~ l u t i o n , r~e~ce~n~t 'studies suggest that rus, and FMS mutations in particu- lar, may represent early events in the pathogen- esis of secondary myeloid neoplasia. Using as- says to detect mutations in X-linked genetic loci, somatic mutations can be identified in circulating blood cells years after exposure to gamma or neutron radiation in atomic bomb survivors.92-"A similar pattern of mutational injury is detected in patients following exposure to therapeutic irradiation and/or chemother- a ~ y In. ~a ~study described earlier,% DNA ex- tracted from peripheral blood specimens of hematologically normal individuals previously treated with chemotherapy for malignant lym- phoma displayed rus point mutations in 9 of 70 cases (13%) tested. These mutations were not identified in archival lymphoma specimens, indi- cating their somatic origin. Eleven patients (16%) harbored FMS mutations at codon 969,3 of whom also had rus mutations. Analysis of clonality using an X-linked probe in 6 of the female patients with mutant proto-oncogene alleles demonstrated a monoclonal pattern in each patient."' N-ras mutations were not de- tected in specimens screened from 18 normal subjects. However, two patients harbored muta- tions in H-rus alleles. Among 111normal volun- 18 LIST AND JACOBS teers screened for FMS mutations, only one erythroid hyperplasia in patients with RARS.97*9R harbored a constitutional mutation at codon This profound disturbance in erythropoiesis 969.8yThese findings indicate that FMS and ras may relate in part to abnormalities of mitochon- mutations occur commonly after conventional drial iron metabolism. Multiple mitochondrial cytotoxic therapy and may be responsible for enzyme defects are demonstrable in RARS that emergence of clonal hematopoiesis in many but give rise to intramitochondrial deposition of not all patients in this setting. Nevertheless, it is insoluble, nonferritin i r ~ n . ' ' ~T, h~is' ~is associ- clear from these data that activating mutations ated with impairment in cell cycle transition of rus and/or FMS alone are insufficient to limiting entry of cells into S phase, defective confer a malignant phenotype. Whether such protein synthesis, and accelerated cell death. mutations increase susceptibility to subsequent Aberrant intercellular junctions demonstrable transforming events and thereby predispose on erythroblasts from patients with dyserythro- individuals to development of MDS must await poietic anemias may further compromise red the results oflongitudinal studies. cell release and contribute to intramedullary hem~lysis."~~"~ BIOLOGIC FEATURES Although impaired progenitor cell growth is a The hematologicabnormalities that characterize MDS reflect an uncoupling of proliferation consistent feature of MDS, CMML remains an important exception. Both JCML and CMML and differentiation in clonal hematopoietic pro- are distinguishedby excessivelyincreased growth genitors. Ineffective hematopoiesis predomi- of CFU-GM in the absence of supplementation nates, accompanied by marrow hypercellularity, with an exogenous source of colony-simulating increased intramedullary cell death, and periph- activity.102.118,119 Analysis of CMML-conditioned eral cyt~penias.~T~h-'e~l*atter are compounded media shows substantially increased levels of by a shortened survival of mature blood ele- interleukind (IL-6) and granulocytelmacro- m e n t ~ . ~ ~P, 'r"ogenitor cell assays have shown phage-colony stimulating factor (GM-CSF).IZO reduced or absent growth of multipotent progen- Antibody neutralization of cytokine activity pro- itors (CFU-GEMM), irrespective of FAB duces near complete inhibition of spontaneous tYPe.105-1R07ecovery of lineage-committed pro- CFU formation.'20~LT2h' ese observations have genitors varies, but generally corresponds to been proposed to support autocrine regulation peripheral blood abnormalities. The abnormali- by GM-CSF and explain the spontaneous prolif- ties in progenitor growth arise principally from eration of CMML progenitors in vitro. How- an intrinsic stem cell defect. Although long- ever, adherent cell depletion prior to culture of term bone marrow cultures have yielded pheno- mononuclear cells from patients with JCML typic abnormalities in the adherent cell layer, abrogates recovery of spontaneous colony- no consistent functional defect in MDS stroma forming units.'" The latter finding supports an is dem~nstrable.'~T'he propensity for abnormal- enhanced sensitivity of CMML myeloid progen- ities in progenitor cell growth to progress and itors to cytokine stimulation and suggests that extend to other myeloid lineages over time GM-CSF is an endogenous paracrine regulator likely relates to the inherent instability of the of myeloid progenitor proliferation in these stem cell clone and accumulation of genetic disorders. The cellular abnormalities that underlie inef- In patients with pure sideroblastic anemia fective hematopoiesis in MDS and how they (RARS), however, dyserythropoiesis and iso- relate to molecular events have not been well- lated abnormalities of erythroid progenitor defined. It is clear from in vitro culture data that growth pred~minate."'-"T~his may explain the impaired response to hematopoietic growth fac- low incidence of leukemic conversion in this tors is a consistent feature accompanying reduced FAB type, although clonal restriction of all recovery of hematopoietic progenitors.lm.'slz Ob- myeloid lineages and, to a variable extent, servationsthat colony growth can be restored with lymphoid progenitors remains d e m ~ n s t r a b l e . ~ . ~ supersaturating concentrations of recombinant Ferrohnetic investigationshave shown the great- growth factors that do not augment growth of est degree of ineffective erythropoiesis and normal progenitors indicates a disturbance in BIOLOGY AND PATHOGENESIS 19 receptor-signal transduction and/or receptor ceded by a myelodysplastic phase (9 of 12;75%) quantity or function.lZ5One mechanism may and treatment-related hematologic disorders (7 relate to activation of growth regulatory genes of 9; 77%) exhibited a comparatively high fre- such as rus, which alter cellular responsiveness quency of P-glycoprotein expression. Although to hemopoietic cytokine~.~'N.~o'~netheless, im- the gene encoding P-glycoprotein (mdrl) is pairment in terminal differentiation and prema- localized to the long arm of chromosome 7,'.'"we ture death of hematopoietic elements may re- found no relation between specific karyotypic late to decreased cellular responsiveness to abnormalities and P-glycoprotein expression. regulatory stimuli. Recent investigations indi- Rather, we found a significant association be- cate that growth factors promote the prolifera- tween P-glycoprotein expression and monocytic tion and differentiation of blood cell precursors and stem cell blast phenotypes. P-glycoprotein by suppressing programmed cell death or apop- was detected in up to 90% of cases expressing tosis,127-I29 thereby sustaining developmental programs for terminal differentiation. Deprivation of hematopoietic cytokines triggers a complex the progenitor cell antigen CD34, compared to 21% in cases lacking CD34-reactivity ( P = 0.001). The latter cohort was principally sequence of events that ultimately results in restricted to patients with CMML or acute DNA fragmentation and cell death. Conceiv- myelomonocyticleukemia. Chaudhary and Ron- ably, apoptosis may provide a physiologic rationale for the high rate of intramedullary cell death and the accompanying cytologicabnormalities identified in MDS. Interestingly, pharmaco- i n ~ o nh'a~v~e subsequently shown that P-glycoprotein is expressed by normal hematopoietic stem cells. These findings indicate that multidrug resistance is an inherent feature of hemato- logic differentiators such as retinoic acid appear poietic stem cells that may be conserved in to act principally through suppression of apopto- neoplastic counterparts. Indeed, CD34 expres- sis.I3ODelineation of the role of this physiologic sion in AML has been linked to inferior rates of process in the biology of MDS warrants investi- complete remission and shorter remission dura- gation and may provide insight for therapeutic tion in patients receivingconventional anthracy- manipulations. cline-containing induction regimen^."^,'^^ The Physiologic features intrinsic to hematopoi- high prevalence of P-glycoprotein expression in etic stem cells may explain the relative insensi- high-risk acute leukemia, its association with tivity of MDS and their leukemia counterparts lineage and stage of differentiation, and the to conventional induction chemotherapy active recently recognized prognostic importance of in de novo AML. Multidrug resistance (MDR) MDR in de novo acute le~kemia'~su' ggest that is a cellular phenotype expressed in drug- MDR may be an important determinant of resistant tumor cell lines and represents an chemotherapy resistance in these disorders po- inherent cellular phenotype in some epithelial tentially amenable to therapeutic manipulation. tissues and corresponding carcinomas. The mdr 1 P-glycoprotein-mediateddrug extrusion is inhib- gene product, P-glycoprotein, serves as a trans- ited in vitro by a number of agents such as membrane drug efflux pump that is induced by verapamil, calmodulin inhibitors, and cyclos- exposure to certain chemical carcinogens and a porin A. Results of a phase 1/11 trial at the broad range of naturally occurring antineoplas- Arizona Cancer Center using cyclosporine as a tic c ~ m p o u n d s . ~B~e~ca. u' ~se~ MDS has been chemosensitizer in patients with high-risk AML linked to xenobiotic exposure, we examined the have shown that this agent can be added to prevalence of P-glycoprotein expression by im- conventional induction therapy without signifi- munocytochemistry in bone marrow specimens cant added toxicity and possibly improved rates from patients with MDS or acute 1 e ~ k e m i a . I ~ ~ of complete remi~sion.'~' P-glycoprotein was detected in 8 of 32 (25%) specimens of de novo MDS and 4 of 19 (21%) CONCLUSION cases of de novo AML. Reactivity was restricted While our knowledge of the pathogenesis of to blast forms and leukemic monocytes, but was MDS continues to evolve, several conclusions otherwise absent from terminally differentiated can be made from studies to date. The major blood cells. In contrast, acute leukemias pre- body of evidence indicates that a concatenation 20 LIST AND JACOBS of factors including host susceptibility, age, sex, cumulative exposure to leukemogens, and other unrecognized factors influence the risk for development of MDS (Fig 1). Preliminary observations indicate that emergence of clonal hematopoiesis as a result of diminished stem cell reserve and/or somatic mutations involving growth regulatory genes can be detected years after genotoxin exposure. Ongoing longitudinal studies will determine whether such changes have an initiating role in the pathogenesis of MDS. Nonetheless, activation of individual cellular oncogenes alone appears insufficient to confer a malignant phenotype, implying additional events are necessarymediators of neoplastic change. Indeed, gross karyotypic aberrations may represent a relatively late event in a series of adaptive changes that reflect genetic instability of the affected clone. Abnormalities at the cellular level have only begun to be explored. Alterations in growth factor receptor number and/or affinity cannot be excluded, and require NI Hematopoiesis Clonal Promotion Progression abnormal karyotype Fig 1. Putative model of the pathogenesisof the myelodysplastic syndromes. investigation. To this end, development of an animal model for MDS should be a focus of future investigations. The myelodysplastic syndromes are an important group of hemopoietic disorders that will assuredly increase in incidence with the continued aging of our population. Understanding the pathobiology of these disorders will no doubt yield critical information concerning fundamental controls of hematopoiesis and provide new avenues for therapeutic manipulation. REFERENCES 1. Bennett JM, Catovsky D, Daniel M-T, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haemato151:189-199,1982 2. 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Fenaux P, Preudhomme C, Stnestienne MH, et al: De novo myelodysplastic syndromes in adults aged 50 or less: A report on 37 cases. Leukem Res 14:1053-1059,1990 9. Brandwein JM, Horsman DE, Eaves AC, et al: Childhood myeloid dysplasia: Suggested classification as myelodysplastic syndromes based on laboratory and clinical findings. Am J Ped Hem Onc 12:63-70, 1990 10. Carroll WL, Morgan R, Glader BE: Childhood bone marrow monosomy-7 syndrome: A familial disorder? J Ped 1071.578-580,1985 11. Weiss K, Stass S, Williams D, et al: Childhood monosomy-7 syndrome: Clinical and in vitro studies. Leukemia 1:97-104,1986 12. Hogge DE, Shannon Kh4, Kalousek DK, et al: Juvenile monosomy-7 syndrome: Evidence that the disease originates in a pluripotent hemopoietic stem cell. Leukem Res 11:705-709,1987 13. Baranger L, Baruchel A, Leverger G, et al: Monosomy-7in childhood hemopoietic disorders. Leukemia 4:345349,1990 14. 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