<i>DUX4r</i>, <i>ZNF384r</i> and <i>PAX5</i>-P80R mutated B-cell precursor acute lymphoblastic leukemia frequently undergo monocytic switch

Abstract

Recently, we described B-cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype with an early switch to the monocytic lineage and the loss of the B-cell immunophenotype, including CD19 expression. Thus far, the genetic background has remained unknown. Among 726 children consecutively diagnosed with BCP-ALL, 8% patients experienced a switch detectable by flow cytometry (FC). Using exome and RNA sequencing, the switch was found to positively correlate with three different genetic subtypes: PAX5 -P80R mutation (five cases with switch of five), rearranged ( DUX4r ) (30 cases of 41) and rearranged ( ZNF384r ) (four cases of ten). Expression profiles or phenotypic patterns correlated with genotypes, but within each genotype no cases who subsequently switched could be indentified. If switching was not taken into account, the B-cell-oriented FC assessment underestimated the minimal residual disease level. For patients with P AX5- P80R, a discordance between FC-determined and polymerase chain reactiondetermined minimal residual disease was found on day 15, resulting from a rapid loss of the B-cell phenotype. Discordance on day 33 was observed in all the DUX4r , PAX5 -P80R and ZNF384r subtypes. Importantly, despite the substantial phenotypic changes, possibly even challenging the appropriateness of BCP-ALL therapy, the monocytic switch was not associated with a higher incidence of relapse and poorer prognosis in patients undergoing standard ALL treatment.

A novel class of ZNF384 aberrations in acute leukemia

“…Notably, besides other myeloid markers, the 3 patients with novel ZNF384 aberrations expressed CD66c, which is rarely expressed in ZNF384r ALL ( Table 1 ). 8 …”

Genetic Alterations in Childhood Acute Lymphoblastic Leukemia: Interactions with Clinical Features and Treatment Response

“…Specifically, compared with PCR MRD, flow MRD is probably more adept at tracking the response of DUX4 ALL. One plausible reason is the tendency for switching of DUX4 leukemia clones to a monocytic lineage [66]. Flow MRD can detect and exclude these monocytic-switched cells.…”

Lineage Plasticity in Cancer: The Tale of a Skin-Walker

“…For instance, imatinib treatment for a CML patient revealed B-lymphoblastic leukemia through bone marrow study and immunophenotyping by flow cytometry [ 151 ]. In a meta-analysis of 726 children who were diagnosed with B-cell precursor ALL, 8% of them exhibited a switch from ALL to monocytic lineage accompanied by loss of B-cell immunophenotype, including CD19 expression [ 152 ]. In another study, lineage switching upon treatment of two B-ALL patients with CAR T-cells was recorded.…”