Unveiling the heterogeneity within chilhood Ph+ acute lymphoblastic leukemia

In the past two decades, childhood acute lymphoblastic leukemia (ALL) cure rate has reached over 80% due to treatment advances, but some resistant ALL subtypes, such as those that carry the Philadelphia (Ph+) chromosome, still don’t respond to therapy. The presence of BCR-ABL in ALL children is correlated to a very poor prognosis, nevertheless, several long-scale studies have shown that Ph+ ALL is heterogeneous in terms of clinical parameters and patients respond differently to the therapy, what suggests the presence of additional mechanisms of leukemogenesis. A set of international studies with large series of patients have shown that an earlier remission after induction with glucocorticoids and intrathecal methotrexate (IT MTX) is correlated to a better outcome. In the present study we looked for secondary genetic lesions in a group of 78 consecutive Ph+ ALL children diagnosed in Italy between 2000 and 2010, specifically studying deletions in the IKZF1 gene and the miRNA profile according to the first therapy response. The IKZF1 gene was studied by PCR, direct sequencing and SNP array and a high incidence of deletions (70%) was detected in our children, specially the d4-7(62%). The miRNA signature was analysed by miRNA array comparing two groups of patients differentiated according to MRD/prednisone response. Particularly miR-221, 222 and miR-125b-2 are highly overexpressed in the poor responder group of patients. We showed in vivo that miR-125b-2 acts as oncogene and increases leukemia aggressiveness. Further studies will be necessary to understand how IKZF1, miR-221,222 and 125b act in cooperation with BCR-ABL to induce leukemia. In the future, novel target therapies can emerge as pro-apoptotic approaches to be added to the anti-tyrosine kinase drugs in order to improve response and survivor in Ph+ ALL.