Bone Marrow Clonogenic Myeloid Progenitors from NPM1-Mutated AML Patients Do Not Harbor the NPM1 Mutation: Implication for the Cell-Of-Origin of NPM1+ AML
Por:
de la Guardia, RD, Gonzalez-Silva, L, Lopez-Millan, B, Rodriguez-Sevilla, JJ, Baroni, ML, Bueno, C, Anguita, E, Vives, S, Palomo, L, Lapillonne, H, Varela, I and Menendez, P
Publicada:
1 ene 2020
Ahead of Print:
9 ene 2020
Resumen:
The cell-of-origin of NPM1- and FLT3-mutated acute myeloid leukemia (AML) is still a matter of debate. Here, we combined in vitro clonogenic assays with targeted sequencing to gain further insights into the cell-of-origin of NPM1 and FLT3-ITD-mutated AML in diagnostic bone marrow (BM) from nine NPM1+/FLT3-ITD (+/-) AMLs. We reasoned that individually plucked colony forming units (CFUs) are clonal and reflect the progeny of a single stem/progenitor cell. NPM1 and FLT3-ITD mutations seen in the diagnostic blasts were found in only 2/95 and 1/57 individually plucked CFUs, suggesting that BM clonogenic myeloid progenitors in NPM1-mutated and NPM1/FLT3-ITD-mutated AML patients do not harbor such molecular lesions. This supports previous studies on NPM1 mutations as secondary mutations in AML, likely acquired in an expanded pool of committed myeloid progenitors, perhaps CD34-, in line with the CD34(-/low) phenotype of NPM1-mutated AMLs. This study has important implications on the cell-of-origin of NPM1+ AML, and reinforces that therapeutic targeting of either NPM1 or FLT3-ITD mutations might only have a transient clinical benefit in debulking the leukemia, but is unlikely to be curative since will not target the AML-initiating/preleukemic cells. The absence of NPM1 and FLT3-ITD mutations in normal clonogenic myeloid progenitors is in line with their absence in clonal hematopoiesis of indeterminate potential.
Filiaciones:
de la Guardia, RD:
Univ Barcelona, Sch Med, Josep Carreras Leukemia Res Inst, Dept Biomed, E-08036 Barcelona, Spain
Gonzalez-Silva, L:
Univ Cantabria, CSIC, Inst Biomed & Biotecnol Cantabria, Santander 39011, Spain
:
Univ Barcelona, Sch Med, Josep Carreras Leukemia Res Inst, Dept Biomed, E-08036 Barcelona, Spain
Rodriguez-Sevilla, JJ:
Univ Barcelona, Sch Med, Josep Carreras Leukemia Res Inst, Dept Biomed, E-08036 Barcelona, Spain
:
Univ Barcelona, Sch Med, Josep Carreras Leukemia Res Inst, Dept Biomed, E-08036 Barcelona, Spain
:
Univ Barcelona, Sch Med, Josep Carreras Leukemia Res Inst, Dept Biomed, E-08036 Barcelona, Spain
Anguita, E:
Univ Complutense Madrid, Hosp Clin San Carlos, Dept Med, Hematol & Hemotherapy Dept,IMDL,IdISSC, E-28040 Madrid, Spain
:
Hosp Badalona Germans Trias & Pujol, ICO, Hematol Dept, Badalona 08916, Spain
Univ Autonoma Barcelona, Josep Carreras Leukemia Res Inst, E-08193 Barcelona, Spain
:
Hosp Badalona Germans Trias & Pujol, ICO, Hematol Dept, Badalona 08916, Spain
Univ Autonoma Barcelona, Josep Carreras Leukemia Res Inst, E-08193 Barcelona, Spain
Lapillonne, H:
Sorbonne Univ, Hosp Armand Trousseau, AP HP, INSERM,CRSA,Haematol Lab, F-75012 Paris, France
Varela, I:
Univ Cantabria, CSIC, Inst Biomed & Biotecnol Cantabria, Santander 39011, Spain
:
Univ Barcelona, Sch Med, Josep Carreras Leukemia Res Inst, Dept Biomed, E-08036 Barcelona, Spain
ISCIII, Ctr Invest Biomed Red Canc CIBER ONC, Barcelona 08036, Spain
ICREA, Barcelona 08010, Spain
Green Published, gold
|