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Natali Rossi thesis

Chronic Myeloid Leukaemia (CML) is a myeloproliferative disorder whose hallmark is represented by the BCR-ABL1 fusion gene. The mechanisms associated with disease progression and development of resistance to treatment are still little understood and so far the best characterised mechanism of resistance is the expansion of a CML clone bearing an amino-acid substitution in the BCR-ABL1 kinase domain (KD). Screening by direct sequencing a large cohort of patients of over 260 CML individuals at various stages of disease, I assessed the incidence of BCR-ABL1 KD mutations and found that, in accordance with previous works, the detection of mutations was strongly linked to clinical resistance. Natali Rossi.

Natali Rossi dissertation 
Furthermore, patients with amino acid substitutions within the P-loop region had commonly presented with features of advanced stages at some point during disease course, accounting for the vast majority of all resistance-associated mutations. To evaluate the impact of the diverse BCR-ABL1 mutations on individual prognosis I stratified the whole cohort of patients on the grounds of disease phase at time of mutation detection and found that events of progression from chronic to advanced phase were mostly represented by patients harbouring KD mutations within the P-loop and gatekeeper domains. Natali Rossi.
 
Natali Rossi resistance to tyrosine-kinase inhibitors
Detection of BCR-ABL1 mutations, however, does not always explain resistance to tyrosine-kinase inhibitors (TKIs). With several studies having indicated a role of certain Src family kinases (SFKs) in the disease progression, we have hypothesised that the ineffectiveness of treatment might be due to the introduction of point mutations within the TK domain of one or other of the three SFKs being implicated in the development and progression of CML, namely Hck, Lyn, and Fyn. Natali Rossi.

Natali Rossi the mutations arising
Systematic evaluation of the mutations arising after treatment with 2G-TKIs has been performed over a subgroup of the initial cohort of CML patients, constituted by 24 non- responder CML patients described as negative for BCR-ABL1 mutations. Screening these patients for SFK Hck, Lyn and Fyn KD mutations, however, could not reveal the presence of any abnormality, suggesting that the clinical heterogeneity of CML requires therefore further investigation of alternative mechanisms responsible of the multifactorial resistance and relapse of CML patients. Natali Rossi.