title: The role of minor subpopulations within the leukemic blast compartment of AML patients at initial diagnosis in the development of relapse.
abstract: The majority of pediatric and younger adult (<60 years) AML patients achieve complete remission. However, 30-40% of patients relapse and display a dismal outcome. Recently we described a frequent instability of type I/II mutations between diagnosis and relapse. Here, we explored the hypothesis that these mutational shifts originate from clonal selection during treatment/disease progression. Subfractions of blasts from initial diagnosis samples were cell sorted and their mutational profiles were compared with those of the corresponding relapse samples of 7 CD34(+) AML patients. At diagnosis, subfractions of the CD45(dim)CD34(+)CD38(dim/-) compartment were heterogeneous in the distribution of mutations, when compared to the whole CD45(dim)CD34(+) blast compartment in 6 out of 7 patients. Moreover, within CD45(dim)CD34(+)CD38(dim/-) fraction of initial samples of 5 of these 6 AML patients, we found evidence for the presence of a minor, initially undetected subpopulation with a specific mutational profile that dominated the bulk of leukemic blasts at relapse. In conclusion, our findings lend support to the AML oligoclonality concept and provide molecular evidence for selection and expansion of a chemo-resistant subpopulation towards development of relapse. These results imply that early detection of pre-existing drug-resistant leukemic subpopulations is crucial for relapse prevention by proper timing of targeted treatment.
authors.affiliation: Department of Pediatric Oncology/Hematology, Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Bachas
authors.forename: G J
authors.initials: GJ
authors.lastname: Schuurhuis
authors.forename: Y G
authors.initials: YG
authors.lastname: Assaraf
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Kwidama
authors.forename: A
authors.initials: A
authors.lastname: Kelder
authors.forename: F
authors.initials: F
authors.lastname: Wouters
authors.forename: A N
authors.initials: AN
authors.lastname: Snel
authors.forename: G J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: J
authors.initials: J
authors.lastname: Cloos
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002999:Clone Cells; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012074:Remission Induction; D025721:WT1 Proteins / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025721:WT1 Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051997:ADP-ribosyl Cyclase 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins