CD34+ cells from AML with mutated NPM1 harbor cytoplasmic mutated nucleophosmin and generate leukemia in immunocompromised mice.

نویسندگان

  • Maria Paola Martelli
  • Valentina Pettirossi
  • Christian Thiede
  • Elisabetta Bonifacio
  • Federica Mezzasoma
  • Debora Cecchini
  • Roberta Pacini
  • Alessia Tabarrini
  • Raffaella Ciurnelli
  • Ilaria Gionfriddo
  • Nicla Manes
  • Roberta Rossi
  • Linda Giunchi
  • Uta Oelschlägel
  • Lorenzo Brunetti
  • Marica Gemei
  • Mario Delia
  • Giorgina Specchia
  • Arcangelo Liso
  • Mauro Di Ianni
  • Francesco Di Raimondo
  • Franca Falzetti
  • Luigi Del Vecchio
  • Massimo F Martelli
  • Brunangelo Falini
چکیده

Acute myeloid leukemia (AML) with mutated NPM1 shows distinctive biologic and clinical features, including absent/low CD34 expression, the significance of which remains unclear. Therefore, we analyzed CD34(+) cells from 41 NPM1-mutated AML. At flow cytometry, 31 of 41 samples contained less than 10% cells showing low intensity CD34 positivity and variable expression of CD38. Mutational analysis and/or Western blotting of purified CD34(+) cells from 17 patients revealed NPM1-mutated gene and/or protein in all. Immunohistochemistry of trephine bone marrow biopsies and/or flow cytometry proved CD34(+) leukemia cells from NPM1-mutated AML had aberrant nucleophosmin expression in cytoplasm. NPM1-mutated gene and/or protein was also confirmed in a CD34(+) subfraction exhibiting the phenotype (CD34(+)/CD38(-)/CD123(+)/CD33(+)/CD90(-)) of leukemic stem cells. When transplanted into immunocompromised mice, CD34(+) cells generated a leukemia recapitulating, both morphologically and immunohistochemically (aberrant cytoplasmic nucleophosmin, CD34 negativity), the original patient's disease. These results indicate that the CD34(+) fraction in NPM1-mutated AML belongs to the leukemic clone and contains NPM1-mutated cells exhibiting properties typical of leukemia-initiating cells. CD34(-) cells from few cases (2/15) also showed significant leukemia-initiating cell potential in immunocompromised mice. This study provides further evidence that NPM1 mutation is a founder genetic lesion and has potential implications for the cell-of-origin and targeted therapy of NPM1-mutated AML.

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عنوان ژورنال:
  • Blood

دوره 116 19  شماره 

صفحات  -

تاریخ انتشار 2010