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.

一组白血病病例进行了辅助测试，包括微阵列研究、核型分析、FISH 和 RNA 测序，以说明克隆进化。每个病例的共同进化病因是明显的同源有丝分裂重组 (HMR)。该队列包括：四例具有单一易位衍生物 (19)t(1;19)(q23.3;p13.3) 的前 B 细胞急性淋巴细胞白血病 (B-ALL)、一例急性髓性白血病 (AML)两个同系物中 11q13.3q23 的旁心倒位被证实为罕见的KMT2A - MAML2基因融合的病例，以及 AML 移植患者复发与 at(6;11)(6q27;q23) 和进化到额外的衍生 6 染色体。PBX1 - TCF3 _t(1;19) B-ALL 亚组中的融合长期以来一直与显示平衡易位 (~25%) 或不平衡单导数 19 (~75%) 的克隆相关。来自 CMA 和 FISH 的证据与 HMR 在PBX1易位断点或更近端的长臂位点启动一致，介导向不平衡形式的进化。这与之前的假设相反，即正常同源物的不分离重复与易位衍生物 1 的丢失或原始三体 1 丢失易位衍生物 1。无关移植供体的复发在微阵列中产生独特的等位基因剂量比具有 t(6;11) KMT2A-AFDN 的AML 患者融合。靠近 6q27 AFDN 的基于 HMR 的进化起始位点融合基因在 6 号染色体的微阵列中很明显，这是已知的致癌融合衍生物。两种 AML 病例中的 HMR 选择驱动因素很可能分别与 6q 和 11q 中致癌融合的 DNA 加倍有关。由于 1;19 病例中的致癌衍生物显然是保留的衍生物 19，因此 1q 中 HMR 克隆进化的选择显然是基于已知的 1q 额外拷贝在 B-ALL 和其他恶性肿瘤中的增殖优势。虽然基于选择的 HMR 可以在驱动基因融合附近的任何位点有效地启动，但易位断裂位点似乎对于许多易位来说是常见的。此外，来自 HMR 进化的证据与远端 11q 突变、许多不平衡的CCND1/IGH易位和双本研究中提出的MAML2/KMT2A表明，在 11q 内的许多重排或突变中，CCND1基因附近存在重组“热点” 。