Copy number alterations in B-cell development genes, drug resistance, and clinical outcome in pediatric B-cell precursor acute lymphoblastic leukemia

Abstract

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is associated with a high frequency of copy number alterations (CNAs) in IKZF1, EBF1, PAX5, CDKN2A/B, RB1, BTG1, ETV6, and/or the PAR1 region (henceforth: B-cell development genes). We aimed to gain insight in the association between CNAs in these genes, clinical outcome parameters, and cellular drug resistance. 71% of newly diagnosed pediatric BCP-ALL cases harbored one or more CNAs in these B-cell development genes. The distribution and clinical relevance of these CNAs was highly subtype-dependent. In the DCOG-ALL10 cohort, only loss of IKZF1 associated as single marker with unfavorable outcome parameters and cellular drug resistance. Prednisolone resistance was observed in IKZF1-deleted primary high hyperdiploid cells (~1500-fold), while thiopurine resistance was detected in IKZF1-deleted primary BCR-ABL1-like and non-BCR-ABL1-like B-other cells (~2.7-fold). The previously described risk stratification classifiers, i.e. IKZF1plus and integrated cytogenetic and CNA classification, both predicted unfavorable outcome in the DCOG-ALL10 cohort, and associated with ex vivo drug cellular resistance to thiopurines, or L-asparaginase and thiopurines, respectively. This resistance could be attributed to overrepresentation of BCR-ABL1-like cases in these risk groups. Taken together, our data indicate that the prognostic value of CNAs in B-cell development genes is linked to subtype-related drug responses.

Molecular profiling refines minimal residual disease‐based prognostic assessment in adults with Philadelphia chromosome‐negative B‐cell precursor acute lymphoblastic leukemia

“…12 16,17 Surprisingly, we did not observe this fact in our B-other cohort nor in the whole series. These results are similar to those reported by the GRAALL group, which identified IKZF1 partial gene deletions as markers of relapse propensity independent of MRD.…”

“…Deletions of IKZF1 and/or EBF1 genes have shown to be related with high levels of MRD and poor prednisone response in pediatric BCP ALL. 16,17 Surprisingly, we did not observe this fact in our B-other cohort nor in the whole series. As children and adolescents and young adults have better response to treatment than adults, we speculate that the MRD positivity attributable to IKZF1 and EBF1 deletions in younger patients mirrors the refractoriness observed for these molecular alterations seen in adults, especially in Ph-like patients.…”

Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols

“…Triggered by these clinical needs, ALL blast genomic analyses aim to identify novel prognostic markers related to patient outcome [13,[15][16][17][18][19][20][21][22][23][24][25][26][27]. Within this frame, individual copy number alterations (CNAs) involving deletions, duplications or amplifications of genes implicated in B-cell differentiation, cell cycle regulation, proliferation and transcription are constantly gaining relevance as potential risk stratification markers [15][16][17][18][19][20][21][22][23][24][25][26][27].…”

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

“…In addition to these events, copy number changes in RUNX1 as a consequence of intra-chromosomal ampli cation (iAMP21), and ERG deletion, have more recently been recognised as initiating events 2 . The biological differences between these subtypes is re ected in their clinical behaviour [3][4][5] .…”