- •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.
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.
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- Relapse of leukemia with loss of mismatched HLA resulting from uniparental disomy after haploidentical hematopoietic stem cell transplantation.Blood, J Am Soc Hematol. 2010; 115 (Apr 15): 3158-3161https://doi.org/10.1182/blood-2009-11-254284
- Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: an evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia.Cancer Genet. 2018; 228 (Dec 1): 236-250https://doi.org/10.1016/j.cancergen.2018.07.004
- Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t (1;19)(q23; p13) or its derivative.J Clin Oncol. 1994; 12 (Dec): 2601-2606https://doi.org/10.1200/JCO.19220.127.116.1101
- Prognostic impact of t (1;19)/TCF3–PBX1 in childhood acute lymphoblastic leukemia in the context of Berlin–Frankfurt–Münster-based protocols.Leuk Lymphoma. 2011; 52 (Jul 1): 1215-1221https://doi.org/10.3109/10428194.2011.565436
- Formation of der (19) t (1;19)(q23; p13) in acute lymphoblastic leukemia.Genes Chromosomes Cancer. 2005; 42 (Feb): 144-148https://doi.org/10.1002/gcc.20133
- Multiple myeloma and the translocation t (11; 14)(q13; q32): a report on 13 cases.Br J Haematol. 1998; 101 (May): 296-301https://doi.org/10.1046/j.1365-2141.1998.00700
- Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.Blood, J Am Soc Hematol. 2009 Jun 11; 113: 6182-6192https://doi.org/10.1182/blood-2008-12-194548
- Novel regions of acquired uniparental disomy discovered in acute myeloid leukemia.Genes Chromosomes Cancer. 2008; 47 (Sep): 729-739https://doi.org/10.1002/gcc.20573
- Copy neutral loss of heterozygosity: a novel chromosomal lesion in myeloid malignancies.Blood, J Am Soc Hematol. 2010; 115 (Apr 8): 2731-2739https://doi.org/10.1182/blood-2009-10-201848
- Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv (11)(q21q23).Genes Chromosomes Cancer. 2007; 46 (Sep): 813-819https://doi.org/10.1002/gcc.20467
- KMT2A-MAML2, a recurrent genetic abnormality in T-cell therapy–related acute lymphoblastic leukemia.J Pediatr Hematol Oncol. 2020; 42 (May 1): e258-e261https://doi.org/10.1097/MPH.0000000000001572
- Inv (11)(q21q23) fuses MLL to the Notch co-activator mastermind-like 2 in secondary T-cell acute lymphoblastic leukemia.Leukemia. 2008; 22 (Sep): 1807-1811https://doi.org/10.1182/blood.V108.11.4284.4284
- Homozygous inv (11)(q21q23) and MLL gene rearrangement in two patients with myeloid neoplasms.Int J Clin Exp Pathol. 2014; 7: 3196
- Pan-cancer landscape analysis reveals recurrent KMT2A-MAML2 gene fusion in aggressive histologic subtypes of thymoma.JCO Precision Oncol. 2020; 4 (Feb): 109-115https://doi.org/10.1200/PO.19.00288
Obama K., Furukawa Y., Tara M., Niina K. Secondary monocytic leukemia with rearrangement of the MLL gene occurring during the course of adult T-cell leukemia. International journal of hematology. 1998 Oct 1;68(3):323–6. doi:10.1016/s0925-5710(98)00076-0.
- Adult de novo acute myeloid leukemia with t (6; 11)(q27; q23) results from cancer and leukemia group B study 8461 and review of the literature.Cancer. 2004; 101 (Sep 15): 1420-1427https://doi.org/10.1002/cncr.20489
- The t (6; 11)(q27; q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases.Leukemia. 1998; 12 (May): 788-791
Published online: March 10, 2023
Accepted: February 27, 2023
Received: November 3, 2021
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