Highlights
- •Case examples of mitotic recombination (MR) mediated clonal evolution are presented and discussed. These include what could be referred to as apparent atypical MR evolution involving the 1;19 (PBX1-TCF3) and 11;14 (CCND1-IGH) translocations. Confirmation of the MR etiology is presented for two patients with KMT2A oncogene related clonal evolution, one of which is complicated by post-transplant allele segregation in the CMA.
ABSTRACT
A cohort of leukemia cases is presented with ancillary testing that includes microarray
studies, karyotyping, FISH, and RNA sequencing to illustrate clonal evolution. Common
evolution etiology with each case is apparent homologous mitotic recombination (HMR).
The cohort includes: four cases of Pre B-cell acute lymphoblastic leukemia (B-ALL)
with a single translocation derivative (19)t(1;19)(q23.3;p13.3), an acute myelogenous
leukemia (AML) case with a paracentric inversion of 11q13.3q23 in both homologues
confirmed as a rare KMT2A-MAML2 gene fusion, and a transplant patient in AML relapse with a t(6;11)(6q27;q23) and
evolution to an additional derivative 6 chromosome. The PBX1-TCF3 fusion in the t(1;19) B-ALL subgroup has long been associated with clones that show
either the balanced translocation (∼25%) or the unbalanced single derivative 19 (∼75%).
Evidence from the CMAs and FISH is consistent with HMR initiating at either the PBX1 translocation breakpoint or at a more proximal long arm site that mediates the evolution
to the unbalanced form. This is contrary to the previous assumptions of either nondisjunction
duplication of the normal homologue with loss of the translocation derivative 1 or
an original trisomy 1 that loses the translocation derivative 1. Relapse from an unrelated
transplant donor created unique allele dosage ratios in the microarray of the AML
patient with the t(6;11) KMT2A-AFDN fusion. An HMR-based evolution initiation site proximal to the 6q27 AFDN fusion gene is evident in the microarray of chromosome 6, the known oncogenic fusion
derivative. The HMR selection driver in both AML cases is very likely associated with
the DNA doubling of the oncogenic fusions in 6q and 11q, respectively. Since the oncogenic
derivatives in the 1;19 cases are clearly the retained derivative 19, selection for
the HMR clonal evolution in 1q is apparently based on the known proliferative advantage
of extra copies of 1q in B-ALL and other malignancies. Although selection-based HMR
can effectively initiate at any site proximal to a driver gene fusion, it appears
that the translocation breaksite is common for many translocations. In addition, evidence
from HMR evolution related distal 11q mutations, numerous unbalanced CCND1/IGH translocations, and the double MAML2/KMT2A presented in this study suggest that a recombinatorial “hot spot” exists near the
CCND1 gene in many rearrangements or mutations within 11q.
Keywords
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Article info
Publication history
Published online: March 10, 2023
Accepted:
February 27,
2023
Received:
November 3,
2021
Identification
Copyright
© 2023 Elsevier Inc. All rights reserved.
