Karyotype Evolution and Phylogenetic Relationships of Cricetulus sokolovi Orlov et Malygin 1988 (Cricetidae, Rodentia) Inferred from Chromosomal Painting and Molecular Data

Sokolov's dwarf hamster (Cricetulus sokolovi) is the least studied representative of the striped hamsters (Cricetulus barabensis species group), the taxonomy of which remains controversial. The species was described based on chromosome morphology, but neither the details of the karyotype nor the phylogenetic relationships with other Cricetulus are known. In the present study, the karyotype of C. sokolovi was examined using cross-species chromosome painting. Molecular and cytogenetic data were employed to determine the phylogenetic position of Sokolov's hamster and to analyze the potential pathways of chromosome evolution in Cricetulus. Both the chromosome and molecular data support the species status of Sokolov's hamster. Phylogenetic analysis of the CYTB data placed C. sokolovi as sister to all other striped hamsters (sequence divergence of 8.1%). FISH data revealed that the karyotype of C. sokolovi is highly rearranged, with the most parsimonious scenario of its origin implying at least 4 robertsonian events and a centromere shift. Comparative cytogenetic data on Cricetinae suggest that their evolutionary history includes both periods of chromosomal conservatism and episodes of rapid chromosomal change.

Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia Harboring t(7;11)(p15;p15)

Introduction: Acute myeloid leukemia (AML) with chromosomal translocation t(7;11)(p15;p15) [t(7;11)], which results in a fusion between NUP98 and HOXA9, is uncommon, and classified as intermediate risk (IR) in National Comprehensive Cancer Network (NCCN) Guidelines. Previous studies have reported that the patients with AML harboring t(7;11) exhibited a worse clinical outcome than the other AML groups. These reports included mostly patients who underwent chemotherapy rather than allogeneic hematopoietic stem cell transplantation (allo-HSCT), and the number of patients in each study was very small. Moreover, the transplant outcomes of patients with AML harboring t(7;11) compared to patients with other AML have not been reported. Therefore, we investigated the transplant outcomes among 91 patients with AML harboring t(7;11) compared to the patients with IR (n=7,308) and poor risk (PR) (n=2,406) AML, except for t(7;11). Moreover, we evaluated the risk factors for survival in patients with AML harboring t(7;11) who underwent allo-HSCT. Patients and Methods: During 1997 and 2014, 91 patients with AML harboring t(7;11) were identified from the nationwide registration data of the Japan Society for Hematopoietic Cell Transplantation. Cytogenetic risk group stratification was performed using the NCCN guidelines for AML in 2016. Univariate and multivariate analysis for survival were performed in all patients cohort and only among patients with AML harboring t(7;11). Univariate models for overall survival (OS) and disease-free survival (DFS) included age at allo-HSCT (age 55 ≥ years vs. 55 < years), sex, performance status (PS) (2-4 vs. 0-1), the hematopoietic cell transplantation-comorbidity index (0-2 vs. ≥ 3), additional chromosomal change, disease status at allo-HSCT (first complete remission [CR]: CR1 vs. second CR:CR2 or non-CR at allo-HSCT), conditioning regimen (total body irradiation [TBI] ≥ 8Gy vs. others), and stem cell source (related donor vs. cord blood or unrelated donor). Factors associated with at least borderline significance (p < 0.20) on univariate analyses were subjected to multivariate analysis. Results: Patient Characteristics We evaluated the clinical characteristics of patients with t(7;11), IR, and PR.The median follow-up period for survivors was 1,124 days (range, 1-8,758). Patients with t(7;11) were younger (median age: 45 vs. 48 vs. 50 years, p<0.01), included more females (49.5 vs. 42.6 vs. 36.2%, p<0.01), and more frequently had PS less than 2 (82.5 vs. 80.2 vs. 76.3%, p<0.01), unrelated donor (40.7 vs. 38.3 vs. 33.9%, p<0.01), received myeloablative TBI (52.4 vs. 42.3 vs. 34.2%, p<0.01), and underwent allo-HSCT at CR1 (48.4 vs. 40.0 vs. 30.9%, p<0.01). Among the patients with t(7;11), 64 (70.3%) had French-American-British classification of M2, and 8 (8.7%) had additional chromosomal change. Transplantation Outcomes At 3 years after allo-HSCT, OS and DFS in the t(7;11) group were 34.4% and 32.8%, respectively, and tended to be lower than those in the IR group after adjusting background characteristics (47.9% [hazard ratio {HR}=0.79, p=0.15] and 43.5% [HR=0.79, p=0.14]). However, OS and DFS in the t(7;11) group were similar to those in the PR group (33.9% [HR=1.18, p=0.3] and 29.2% [HR=1.18, p=0.27]) (Figure 1). Interestingly, the estimated cumulative incidence of relapse (CIR) at 3 years in the t(7;11) group was higher than that in the IR group (35.8% vs. 21.1% [HR=0.59, p<0.01]), but comparable to that in the PR group (29.8% [HR=0.8, p=0.24]) (Figure 2). In contrast, the estimated cumulative incidence of transplant-related mortality (TRM) in the t(7;11) group was similar to that in the IR/PR group (26.4% vs. 34.2% [HR=1.18, p=0.52] and 43.8% [HR=1.55, p=0.09]). In multivariate analysis among the t(7;11) group, the only factor influencing DFS was disease status (CR2: HR=2.78 [p=0.03], non-CR: HR=2.23 [p<0.01]) (Figure 3). In addition, patients in the CR1 group showed a lower CIR (21.0%) compared with patients in the CR2 or non-CR group (45.0% [HR=2.25, p=0.16], 44.9% [HR=2.31, p=0.03]) at 2 years. Conclusion: OS and DFS for the AML with t(7;11) following allo-HSCT were lower than those in the IR group due to higher CIR, but similar to those in the PR group. Among the patients with AML harboring t(7;11), disease status was the only independent prognostic factor for survival in the setting of allo-HSCT. Allo-HSCT at CR1 may overcome the poor prognosis of AML with t(7;11). Disclosures No relevant conflicts of interest to declare.

Different patterns of Robertsonian fusion pairing in Bovidae and the house mouse: the relationship between chromosome size and nuclear territories

SummaryUsing a dataset of karyotypic changes reported for bovids and the house mouse (Mus musculus domesticus) together with information from the cattle (Bos taurus) and mouse genomes, we examined two principal variables that have been proposed to predict chromosomal positioning in the nucleus, chromosome size and GC content. These were expected to influence the distribution of Robertsonian (Rb) fusions, the predominant mode of chromosomal change in both taxa. We found the largest chromosomes to be most frequently involved in fusions in bovids, and confirm earlier reports that chromosomes of intermediate size were the most frequent fusers in mice. We then tested whether chromosomal positioning can explain Rb fusion frequencies. We classified chromosomes into groups by size and considered the frequency of interactions between specific groups. Among the interactions, mouse chromosomes showed a slight tendency to fuse with neighbouring chromosomes, in line with expectations of chromosomal positioning, but also resembling predictions from meiotic spindle-induced bias. Bovids, on the other hand, showed no trend in interactions, with small chromosomes being the least frequent partner for all size classes. We discuss the results in terms of nuclear organization at various cell cycle stages and the proposed mechanisms of Rb fusion formation, and note that the difference can be explained by (i) considering bovid species generally to be characterized by a greater intermingling of chromosomal size classes than the house mouse, or (ii) by the vastly different timescales underpinning their evolutionary histories.

Chromosome painting among Proboscidea, Hyracoidea and Sirenia: support for Paenungulata (Afrotheria, Mammalia) but not Tethytheria

Despite marked improvements in the interpretation of systematic relationships within Eutheria, particular nodes, including Paenungulata (Hyracoidea, Sirenia and Proboscidea), remain ambiguous. The combination of a rapid radiation, a deep divergence and an extensive morphological diversification has resulted in a limited phylogenetic signal confounding resolution within this clade both at the morphological and nucleotide levels. Cross-species chromosome painting was used to delineate regions of homology between Loxodonta africana (2 n =56), Procavia capensis (2 n =54), Trichechus manatus latirostris (2 n =48) and an outgroup taxon, the aardvark ( Orycteropus afer , 2 n =20). Changes specific to each lineage were identified and although the presence of a minimum of 11 synapomorphies confirmed the monophyly of Paenungulata, no change characterizing intrapaenungulate relationships was evident. The reconstruction of an ancestral paenungulate karyotype and the estimation of rates of chromosomal evolution indicate a reduced rate of genomic repatterning following the paenungulate radiation. In comparison to data available for other mammalian taxa, the paenungulate rate of chromosomal evolution is slow to moderate. As a consequence, the absence of a chromosomal character uniting two paenungulates (at the level of resolution characterized in this study) may be due to a reduced rate of chromosomal change relative to the length of time separating successive divergence events.

Chromosomal phylogeny of Robertsonian races of the house mouse on the island of Madeira: testing between alternative mutational processes

The ancestral karyotype of the house mouse (Mus musculus) consists of 40 acrocentric chromosomes, but numerous races exist within the domesticus subspecies characterized by different metacentric chromosomes formed by the joining at the centromere of two acrocentrics. An exemplary case is present on the island of Madeira where six highly divergent chromosomal races have accumulated different combinations of 20 metacentrics in 500–1000 years. Chromosomal cladistic phylogenies were performed to test the relative performance of Robertsonian (Rb) fusions, Rb fissions and whole-arm reciprocal translocations (WARTs) in resolving relationships between the chromosomal races. The different trees yielded roughly similar topologies, but varied in the number of steps and branch support. The analyses using Rb fusions/fissions as characters resulted in poorly supported trees requiring six to eight homoplasious events. Allowance for WARTs considerably increased nodal support and yielded the most parsimonious trees since homoplasy was reduced to a single event. The WART-based trees required five to nine WARTs and 12 to 16 Rb fusions. These analyses provide support for the role of WARTs in generating the extensive chromosomal diversification observed in house mice. The repeated occurrence of Rb fusions and WARTs highlights the contribution of centromere-related rearrangements to accelerated rates of chromosomal change in the house mouse.