3138 – HIGH CHROMOSOME INSTABILITY ACROSS ANEUPLOID SUBTYPES OF CHILDHOOD B-CELL ALL AND POTENTIAL ASSOCIATION WITH DISEASE PROGRESSION IN PDX MODELS.
Oscar Molina, namitha Thampi, Juan Trincado, Carmen Ortega-Sabater, Gabriel Fernández-Calvo, Paola Romecín, Alba Martínez-Moreno, Talía Velasco-Hernández, Meritxell Vinyoles, Victor Pérez-García, Angelika Merkel, Isabel Granada, Mireia Camós, Jose Fuster, Paola Ballerini, Franco Locatelli, Charles Mullighan, Clara Bueno, Pablo Menéndez
EXP HEMATOL
B-cell acute lymphoblastic leukemia (B-ALL) is the most common cancer in children and 35% of patients show aneuploidy. Specific aneuploid subtypes in B-ALL have an important prognostic value and are classified according to chromosome numbers in high-Hyperdiploid (HeH), low-Hypodiploid (HoL) and near-haploid (nHap). Aneuploidy frequently associates with chromosome instability (CIN), a common phenomenon in human cancers that usually correlates with poor prognosis. However, little is known about CIN in aneuploid subtypes of B-ALL. Here, we aimed to elucidate the presence and levels of CIN in the distinct aneuploid B-ALL subtypes and its specific contribution to disease outcome.
Computational analyses in a large cohort of B-ALL samples (n=227) revealed higher levels of chromosome number heterogeneity (CNH) in aneuploid samples. Single-cell DNA-sequencing B-ALL samples confirmed high-degree of CNH in aneuploid B-ALL and revealed a strong correlation between aneuploidy and CNH. In addition, euploid, HeH, HoL and nHap primary B-ALL samples (n=12, 3 samples/group) were xenotransplanted in NSG mice to study the CIN phenotype and its contribution to disease progression (n=57 patient-derived xenografted (PDX) mice). Our results showed significant higher levels of mitosis defects, and a strong positive correlation between chromosome missegregation and CNH among B-ALL subtypes (p< 0.0001), unequivocally demonstrating the presence of high levels of CIN across aneuploid subtypes of B-ALL. Remarkably, the levels of chromosome mis-segregation and CNH negatively correlate with overall survival rates in PDX.
Collectively, our results suggest that the levels of CIN in aneuploid subtypes of B-ALL are associated with disease progression. Ongoing studies will shortly elucidate the CIN signature in B-ALL which will be instrumental to better stratify patients and/or as a therapeutic target.