@article{Simona Soverini_Antonella Vitale_Angela Poerio_Alessandra Gnani_Sabrina Colarossi_Ilaria Iacobucci_Giuseppe Cimino_Loredana Elia_Annalisa Lonetti_Marco Vignetti_Stefania Paolini_Giovanna Meloni_Valeria di Maio_Cristina Papayannidis_Marilina Amabile_Anna Guarini_Michele Baccarani_Giovanni Martinelli_Robin Foà_2011, place={Pavia, Italy}, title={Philadelphia-positive acute lymphoblastic leukemia patients already harbor BCR-ABL kinase domain mutations at low levels at the time of diagnosis}, volume={96}, url={https://haematologica.org/article/view/5934}, DOI={10.3324/haematol.2010.034173}, abstractNote={<strong>Background</strong> In patients with Philadelphia-positive acute lymphoblastic leukemia, resistance to treatment with tyrosine kinase inhibitors is frequent and most often associated with the development of point mutations in the <em>BCR-ABL</em> kinase domain. We aimed to assess: (i) in how many patients <em>BCR-ABL</em> kinase domain mutations are already detectable at relatively low levels at the time of diagnosis, and (ii) whether mutation detection correlates with subsequent response to therapy.<strong>Design and Methods</strong> We retrospectively analyzed samples collected at diagnosis from 15 patients with Philadelphia-positive acute lymphoblastic leukemia who subsequently received tyrosine kinase inhibitor therapy (dasatinib) by cloning the <em>BCR-ABL</em> kinase domain in a bacterial vector and sequencing 200 independent clones per sample.<strong>Results</strong> Mutations at relatively low levels (2–4 clones out of 200) could be detected in all patients – eight who relapsed and seven who achieved persistent remission. Each patient had evidence of two to eight different mutations, the majority of which have never been reported in association with resistance to tyrosine kinase inhibitors. In two patients out of six who relapsed because of a mutation, the mutation (a T315I) was already detectable in a few clones at the time of diagnosis. On the other hand, a patient who was found to harbor an F317L mutation is in persistent remission on dasatinib.<strong>Conclusions</strong> Our results suggest that the <em>BCR-ABL</em&gt; kinase domain is prone to randomly accumulate point mutations in Philadelphia-positive acute lymphoblastic leukemia, although the presence of these mutations in a relatively small leukemic subclone does not always preclude a primary response to tyrosine kinase inhibitors.}, number={4}, journal={Haematologica}, author={Simona Soverini and Antonella Vitale and Angela Poerio and Alessandra Gnani and Sabrina Colarossi and Ilaria Iacobucci and Giuseppe Cimino and Loredana Elia and Annalisa Lonetti and Marco Vignetti and Stefania Paolini and Giovanna Meloni and Valeria di Maio and Cristina Papayannidis and Marilina Amabile and Anna Guarini and Michele Baccarani and Giovanni Martinelli and Robin Foà}, year={2011}, month={Mar.}, pages={552-557} }