Pathogenesis Fanconi anemia

1 pathogenesis

1.1 myelodysplastic syndromes
1.2 acute myeloid leukemia
1.3 bone marrow failure
1.4 molecular basis
1.5 spermatogenesis
1.6 neural stem cell homeostasis

pathogenesis

clinically, hematological abnormalities serious symptoms in fa. age of 40, 98% of fa patients have developed type of hematological abnormality. however, few cases have occurred in older patients have died without ever developing them. symptoms appear progressively, , lead complete bone marrow failure. while @ birth, blood count normal, macrocytosis/megaloblastic anemia, defined unusually large red blood cells, first detected abnormality, within first decade of life (median age of onset 7 years). within next 10 years, on 50% of patients presenting haematological abnormalities have developed pancytopenia, defined abnormalities in 2 or more blood cell lineages. in contrast diamond–blackfan anemia, affects erythrocytes, , shwachman–diamond syndrome, causes neutropenia. commonly, low platelet count (thrombocytopenia) precedes low neutrophil count (neutropenia), both appearing relative equal frequencies. deficiencies cause increased risk of hemorrhage , recurrent infections, respectively.

as fa known affect dna repair, nonhomologous end joining, , given current knowledge dynamic cell division in bone marrow, finding patients more develop bone marrow failure, myelodysplastic syndromes, , acute myeloid leukemia (aml) not surprising.

myelodysplastic syndromes

mdss, formerly known preleukemia, group of bone marrow neoplastic diseases share many of morphologic features of aml, important differences. first, percentage of undifferentiated progenitor cells, blast cells, less 20%, considerably more dysplasia, defined cytoplasmic , nuclear morphologic changes in erythroid, granulocytic, , megakaryocytic precursors, seen in cases of aml. these changes reflect delayed apoptosis or failure of programmed cell death. when left untreated, mds can lead aml in 30% of cases. due nature of fa pathology, mds diagnosis cannot made solely through cytogenetic analysis of marrow. indeed, when morphologic analysis of marrow cells performed, diagnosis of mds can ascertained. upon examination, mds-afflicted fa patients show many clonal variations, appearing either prior or subsequent mds. furthermore, cells show chromosomal aberrations, frequent being monosomy 7 , partial trisomies of chromosome 3q 15. observation of monosomy 7 within marrow correlated increased risk of developing aml , poor prognosis, death ensuing within 2 years (unless prompt allogeneic hematopoietic progenitor cell transplant option).

acute myeloid leukemia

fa patients @ elevated risk development of aml defined presence of 20% or more of myeloid blasts in marrow or 5 20% myeloid blasts in blood. of subtypes of aml can occur in fa exception of promyelocytic. however, myelomonocytic , acute monocytic common subtypes observed. many mds patients diseases evolve aml if survive long enough. furthermore, risk of developing aml increases onset of bone-marrow failure.

although risk of developing either mds or aml before age of 20 27%, risk increases 43% age of 30 , 52% age of 40. historically, marrow transplant, quarter of fa patients diagnosed mds/als have died mds/als-related causes within 2 years, although more recent published evidence suggests earlier allogeneic hematopoietic progenitor cell transplantation in children fa leading better outcomes on time.

bone marrow failure

the last major haematological complication associated fa bone marrow failure, defined inadequate blood cell production. several types of failure observed in fa patients, , precede mds , aml. detection of decreasing blood count first sign used assess necessity of treatment , possible transplant. while fa patients responsive androgen therapy , haemopoietic growth factors, these have been shown promote leukemia, in patients clonal cytogenetic abnormalities, , have severe side effects, including hepatic adenomas , adenocarcinomas. treatment left bone marrow transplant; however, such operation has relatively low success rate in fa patients when donor unrelated (30% 5-year survival). is, therefore, imperative transplant hla-identical sibling. furthermore, due increased susceptibility of fa patients chromosomal damage, pretransplant conditioning cannot include high doses of radiation or immunosuppressants, increased chances of patients developing graft-versus-host disease. if precautions taken, , marrow transplant performed within first decade of life, two-year probability of survival can high 89%. however, if transplant performed @ ages older 10, two-year survival rates drop 54%.

a recent report zhang et al. investigates mechanism of bone marrow failure in fancc-/- cells. hypothesize , demonstrate continuous cycles of hypoxia-reoxygenation, such seen haemopoietic , progenitor cells migrate between hyperoxic blood , hypoxic marrow tissues, leads premature cellular senescence , therefore inhibition of haemopoietic function. senescence, apoptosis, may constitute major mechanism of haemopoietic cell depletion occurred in bone marrow failure.

molecular basis

recombinational repair of dna double-strand damage - key steps. atm (atm) protein kinase recruited , activated dna double-strand breaks. dna double-strand damages activate fanconi anemia core complex (fanca/b/c/e/f/g/l/m). fa core complex monoubiquitinates downstream targets fancd2 , fanci. atm activates (phosphorylates) chek2 , fancd2 chek2 phosphorylates brca1. ubiquinated fancd2 complexes brca1 , rad51. palb2 protein acts hub, bringing brca1, brca2 , rad51 @ site of dna double-strand break, , binds rad51c, member of rad51 paralog complex rad51b-rad51c-rad51d-xrcc2 (bcdx2). bcdx2 complex responsible rad51 recruitment or stabilization @ damage sites. rad51 plays major role in homologous recombinational repair of dna during double strand break repair. in process, atp dependent dna strand exchange takes place in single strand invades base-paired strands of homologous dna molecules. rad51 involved in search homology , strand pairing stages of process.

there 19 genes responsible fa, 1 of them being breast-cancer susceptibility gene brca2. involved in recognition , repair of damaged dna; genetic defects leave them unable repair dna. fa core complex of 8 proteins activated when dna stops replicating because of damage. core complex adds ubiquitin, small protein combines brca2 in cluster repair dna (see figure recombinational repair of dna double-strand damage). @ end of process, ubiquitin removed.

recent studies have shown 8 of these proteins, fanca, -b, -c, -e, -f, -g, -l , –m assemble form core protein complex in nucleus. according current models, complex moves cytoplasm nucleus following nuclear localization signals on fanca , fance. assembly activated replicative stress, particularly dna damage caused cross-linking agents (such mitomycin c or cisplatin) or reactive oxygen species (ros) detected fancm protein.

following assembly, protein core complex activates fancl protein acts e3 ubiquitin-ligase , monoubiquitinates fancd2.

monoubiquitinated fancd2, known fancd2-l, goes on interact brca1/brca2 complex (see figure recombinational repair of dna double-strand damage). details not known, similar complexes involved in genome surveillance , associated variety of proteins implicated in dna repair , chromosomal stability. crippling mutation in fa protein in complex, dna repair less effective, shown response damage caused cross-linking agents such cisplatin, diepoxybutane , mitomycin c. bone marrow particularly sensitive defect.

in pathway responding ionizing radiation, fancd2 thought phosphorylated protein complex atm/atr activated double-strand dna breaks, , takes part in s-phase checkpoint control. pathway proven presence of radioresistant dna synthesis, hallmark of defect in s phase checkpoint, in patients fa-d1 or fa-d2. such defect readily leads uncontrollable replication of cells , might explain increase frequency of aml in these patients.

spermatogenesis

in humans, infertility 1 of characteristics of individuals mutational defects in fanc genes. in mice, spermatogonia, preleptotene spermatocytes, , spermatocytes in meiotic stages of leptotene, zygotene , pachytene enriched fanc proteins. finding suggests recombinational repair processes mediated fanc proteins active during germ cell development, particularly during meiosis, , defects in activity can lead infertility.

neural stem cell homeostasis

microphthalmia , microcephaly frequent congenital defects in fa patients. loss of fanca , fancg in mice causes neural progenitor apoptosis both during developmental neurogenesis , later during adult neurogenesis. leads depletion of neural stem cell pool aging. of fanconi anemia phenotype might interpreted reflection of premature aging of stem cells.