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The article is dedicated to the anniversary of Professor, Dr. Sci. Valentina G. Kuznetsova, Editor-in-Chief and co-founder of the journal "Comparative Cytogenetics". V. Kuznetsova is the principal researcher at the Zoological Institute of the Russian Academy of Sciences, Head of the Department of Karyosystematics. Under her leadership, many Russian and foreign cytogeneticists have successfully defended their dissertations. Today, Valentina Kuznetsova is one of the world's leading experts in the field of comparative cytogenetics and karyosystematics of insects. The list of her publications includes 200 scientific articles, chapters in books and collective monographs.
The anuran species group Physalaemus gracilis comprises six species, and variation in the location of nucleolus organizer regions (NORs) was observed across the four species that have been karyotyped to date. The NORs are located interstitially on chromosome 8 of P. carrizorum Cardozo et Pereyra, 2018, and P. lisei Braun et Braun, 1977, terminally on chromosome 8 of P. gracilis (Boulenger, 1883), and terminally on chromosome 10 of P. barrioi Bokermann, 1967. To contribute to the comparative analysis of this group, including the assessment of the hypothesis of homology among these NOR-bearing chromosomes, we described the karyotype of P. evangelistai Bokermann, 1967, and expanded the cytogenetic analyses of P. carrizorum, P. lisei, and P. barrioi. We used classical cytogenetic techniques and mapped, by fluorescent in situ hybridization (FISH), two repetitive sequences: the PcP190 satellite DNA and the U2 snRNA gene. Physalaemus evangelistai exhibited a 2n = 22 karyotype, with meta- and submetacentric chromosomes, which corresponds to the typical karyotypic configuration of the genus. We found an interstitial heterochromatin DAPI-positive band on the short arm of the NOR-bearing chromosomes 8 of P. evangelistai and P. carrizorum from Palmas-PR, and chromosome 10 of P. barrioi, which corroborates the hypothesis that these chromosomes are homologous. In P. evangelistai, an additional NOR was observed on chromosome 9 of females. Moreover, the karyotype of P. carrizorum from Palmas-PR differed from that previously described for P. carrizorum from Misiones, particularly in the number of PcP190 clusters and intrachromosomal position of the NOR on chromosome 8. Specimens from Palmas-PR showed a terminal NOR on chromosome 8 and PcP190 clusters on chromosomes 1 and 3, whereas those from Misiones had an interstitial/pericentromeric NOR on chromosome 8 and a single PcP190 cluster on chromosome 3. Further analyses are still needed to assess whether these cytogenetic differences represent interspecific variation.
Bothriurus Peters, 1861 is one of the most diverse genera within the family Bothriuridae. However, to date, only five species have been analyzed using a cytogenetic approach. In this study, for the first time, two populations of Bothriurus asper Pocock, 1893 and nine populations of Bothriurus rochai Mello-Leitão, 1932, two species from northeastern Brazil, were analyzed with respect to diploid number, chromosomal behavior during meiosis, and the localization of heterochromatin and nucleolus organizer regions (NORs). For B. asper, a diploid number of 2n = 30 was recorded in geographically distant populations, whereas B. rochai exhibited intraspecific variation in diploid number (2n = 16 and 2n = 18), representing the lowest diploid numbers ever reported for the family Bothriuridae. Despite the variability in diploid number, the number and localization of NORs remained stable among the populations of B. rochai. When comparing heterochromatin patterns between the two species, larger blocks of constitutive heterochromatin were observed in B. asper than in B. rochai. Variation in the amount of heterochromatin among populations of B. rochai was also observed; in this case, the population with the lowest amount of heterochromatin also exhibited the greatest variation in post-pachytene cell configurations. This is the first study to cytogenetically analyze multiple populations of species within the genus Bothriurus, and it significantly expands the karyotypic information available for scorpions with monocentric chromosomes.
The optimal frontline therapy for acute myeloid leukemia (AML) with very high-risk cytogenetics (vHRC)-defined by complex karyotype (CK), monosomal karyotype (MK), or inv(3)/t(3;3)-remains uncertain. We retrospectively analyzed 358 newly diagnosed AML-vHRC cases treated at five academic centers (2014-2024), stratified by intensive chemotherapy (IC) vs hypomethylating agent plus venetoclax (HMA+ven). Cytogenetic features included CK in 90.2%, MK in 64%, and inv(3)/t(3;3) in 9.8%; TP53 mutations occurred in 51%. Frontline therapy was IC in 40% and HMA+ven in 60%, with a median age of 67 years (range, 22-92). Median overall survival (OS) for AML-vHRC was 8 months compared with 31 months for non-vHRC AML (P < .0001). Composite complete remission (cCR) rates were similar with IC vs HMA+ven (55% vs 54%, P = .91). Patients with inv(3)/t(3;3) had inferior responses (cCR 36%) compared with CK/MK-AML (67%; P < .001). No OS differences by frontline regimen were observed among patients aged 60-75 years (7.7 vs 6.6 months, P = 0.43), those with TP53-mutated disease (8.1 vs 5.8 months, P = .17), or following allogeneic hematopoietic stem cell transplantation (alloHSCT; 35 vs 25 months, P = .56). On multivariable analysis, older age (HR 1.02, P = .0003), inv(3)/t(3;3) (HR 2.12, P = .0002), and TP53mt (HR 2.07, P < .0001) independently predicted inferior OS, whereas alloHSCT improved OS (HR 0.42, P < .0001); frontline regimen (HMA+ven vs IC) was not associated with OS (HR 0.84, P = .2814). In AML-vHRC, IC and HMA+ven yield comparable remission and survival outcomes. Given equivalent efficacy and similar early mortality, HMA+ven represents a reasonable frontline option for patients aged 60-75 years, those with TP53mt disease, and patients intended for alloHSCT.
For decades, the "death of cancer cytogenetics" has been repeatedly proclaimed and has grown louder in the era of omics. However, cytogenetics continues to evolve, retaining its central role in the study of chromosomes. From the microscopic visualization of numerical and structural aberrations using staining and banding techniques, the field has steadily incorporated new methodologies, including fluorescence in situ hybridization, array comparative genomic hybridization, high-throughput sequencing, and, most recently, optical genome mapping. These approaches have revealed unprecedented details of chromosome structure and behavior, uncovered catastrophic genomic events in cancer, and given rise to new concepts such as cytogenomics and chromosomics. Although cytogenetics is sometimes viewed as synonymous with chromosome banding, its scope, namely the study of chromosome structure and behavior, extends far beyond any single method. Chromosomes remain indispensable for understanding genome architecture, chromosomal instability, and fusion-gene mechanisms in neoplasia, irrespective of the technologies applied. Rooted in its past yet continually branching outwards with each scientific advance, today's cytogenetics integrates classical and modern approaches, carrying forward the legacy of chromosome banding while adopting genome-wide technologies. These developments underscore the enduring importance of cytogenetics for interpreting the structural complexity of cancer genomes. This review aims to demonstrate that cytogenetics, far from being obsolete, remains a vital component of modern cancer research by highlighting essential insights into chromosome structure, genome architecture, and fusion-gene mechanisms in the era of -omics.
Comparative fluorescence in situ hybridization (FISH) mapping, particularly chromosome painting, was first developed in mammalian systems and generated much of the foundational knowledge on chromosomal relationships among diverse mammalian species prior to the genome sequencing era. In plants, the advent of region- and chromosome-specific FISH probes based on massively synthesized oligonucleotides (oligos) has greatly expanded the utility of FISH in cytogenetic mapping. We developed oligo-based barcode-FISH and chromosome painting probes in the model citrus species Citrus maxima and applied them to 13 species from the Aurantioideae subfamily of Rutaceae. All 13 species retained complete chromosomal synteny with C. maxima despite ∼20 million years of divergence. Remarkably, these probes were also successfully applied to Boenninghausenia albiflora (Rutoideae subfamily), which diverged from citrus species ∼52 million years ago. Comparative FISH mapping revealed the mechanism underlying its change in basic chromosome number from 9 to 10 and identified three distinct chromosomal translocation events in B. albiflora. Together, these results demonstrate that oligo-based FISH probes developed in a model plant species can be effectively applied across deeply diverged lineages, enabling the rapid reconstruction of chromosomal evolutionary histories on timescales previously inaccessible to plant cytogenetics.
Background/Objectives: Gonadal germ cell tumors (GCTs) arise in the testis and ovary from primordial germ cells. Despite shared origins, they display distinct molecular and genetic features. Understanding these differences is essential for clarifying tumor pathogenesis and improving diagnostic and therapeutic strategies. This review aims to compare these features and to better define the biological differences between testicular and ovarian GCTs. Methods: We reviewed cytogenetic alterations, epigenetic modifications, and somatic mutations reported in testicular and ovarian GCTs. Comparative analysis was performed to identify common and site-specific mechanisms. Results: Isochromosome 12p is a hallmark of testicular GCTs, while ovarian GCTs show diverse chromosomal changes. DNA methylation and other epigenetic marks differ by tumor subtype and gonadal origin. Somatic mutations affect pathways regulating cell cycle, pluripotency, and differentiation, with overlapping and unique patterns between testicular and ovarian tumors. Collectively, these findings define a molecular framework that explains both shared biology and gonadal-specific divergence in GCTs. Conclusions: Understanding molecular similarities and differences across gonadal GCTs can refine classification, guide biomarker discovery, and inform translational research. This comparative perspective highlights core pathogenetic mechanisms and gonadal-specific features relevant to clinical and experimental oncology.
In the Mediterranean region, for over 150 species belonging to the subtribe Orchidinae, chromosome number has been documented and found to range from 2n = 32 to 2n = 42. This work renews and updates chromosome numbers and reports a karyomorphological comparison between species with 32 or 36 chromosomes and species with 40 or 42 chromosomes. Notably, in the 32,36-chromosome group, species within the genus Anacamptis s.l. show substantially similar karyomorphology, although some species exhibit differences in chromosome structure and heterochromatin distribution. In contrast, in the 40,42-chromosome group, the chromosomes are comparatively smaller and therefore difficult to sort into karyotypes when standard staining techniques are used. However, the two groups display distinct heterochromatin patterns, particularly in centromeric and telomeric regions. Given the growing body of information in this field, a review of current cytogenetic knowledge is warranted. In this report, the authors present classical and molecular cytogenetic data and highlight important aspects of karyotypic evolution in Orchidinae. Traditional karyotypic analysis, based on stained mitotic chromosomes, can be used to distinguish and identify taxonomic groups. Karyomorphometric studies in particular reveal subtle differences between closely related chromosome sets within Orchidinae. Furthermore, wide variation among genera in terms of heterochromatin content was observed. Further comparative data between the two above-mentioned groups are summarized.
This review synthesizes the most significant advances and innovations in the cytogenetic study of Neotropical fishes, with emphasis on recurrent chromosomal patterns, evolutionary mechanisms, and the integration of modern genomic tools. The Neotropical region, which harbors more than 12,000 fish species, exhibits not only extraordinary taxonomic richness but also remarkable chromosomal diversity. Chromosomal rearrangements have been associated with speciation and ecological adaptation in both freshwater and marine lineages. Modern techniques, including fluorescence in situ hybridization, chromosome painting, and comparative genomic hybridization (CGH), have substantially improved our ability to resolve morphologically indistinguishable species and clarify their evolutionary relationships. When integrated with phylogenetic and genomic approaches, cytogenetics becomes a robust framework for exploring biodiversity and chromosomal evolution within the complex Neotropical fauna. Despite these advances, substantial challenges remain, particularly the scarcity of cytogenetic data for many taxa and regions. Future research, driven by high-throughput genomic technologies, is expected to deepen our understanding of chromosomal evolution and to support conservation efforts for this rich but increasingly threatened fish fauna.
The near-simultaneous publication of the World Health Organization (WHO) 5th Edition classification of hematolymphoid tumors (WHO-HAEM5) and the International Consensus Classification (ICC) in 2022 represents a pivotal moment in the taxonomy of myeloid neoplasms. Both systems emphasize integration of morphology, cytogenetics, and molecular genetics, yet they diverge in several clinically meaningful areas, including blast thresholds for acute myeloid leukemia (AML), definition of the myelodysplastic syndrome (MDS)-AML interface, and categorization of TP53-mutated disease [TP53mut MN] [1-3]. These differences extend beyond nomenclature, influencing prognostic stratification, therapeutic decision-making, and eligibility for clinical trials [4-7]. Recent comparative cohort studies demonstrate substantial reclassification rates, particularly among MDS with excess blasts, AML with myelodysplasia-related features, and TP53-mutated neoplasms, with prognosis driven largely by underlying molecular features rather than blast percentage alone [8-11]. This review provides a comprehensive comparison of WHO-HAEM5 and ICC 2022, synthesizes emerging real-world outcome data, and discusses implications for diagnostic practice, harmonization efforts, and future refinement of myeloid neoplasm classification [12-14].
KIT mutations are recurrent genetic alterations in myeloid neoplasms (MNs), with the D816 hot-spot variant recognized as a poor prognostic marker in acute myeloid leukemia (AML) with RUNX1::RUNX1T1 and as a diagnostic criterion for systemic mastocytosis (SM). In contrast, the clinical and biological relevance of KIT mutations outside codon 816 remains insufficiently characterized. We retrospectively analyzed 40 MNs with pathogenic KIT mutations, comparing 26 cases harboring D816 variants to 14 cases with non-D816 changes. Clinicopathologic features, cytogenetics, molecular profiles, immunohistochemical data, and survival outcomes were evaluated. The two groups showed similar distributions of MN subtypes and cytogenetic abnormalities. However, the non-D816 group exhibited significantly lower mast-cell burden by CD117 immunohistochemistry and no cases of SM, whereas 31% of D816 cases showed concurrent or subsequent SM. D816 cases displayed more complex co-mutational profiles and a higher rate of KIT acquisition as a secondary event. Non-D816 cases demonstrated significantly longer overall survival. In the subset of AML with t(8;21), D816 variants trended toward inferior survival compared with non-D816 variants. Our findings suggest that non-D816 KIT mutations are associated with a less aggressive clinical phenotype, lower mast-cell differentiation, and improved outcomes. These results support a biologically distinct role of non-D816 KIT variants in MNs and highlight the need for refined risk stratification incorporating KIT variant classes.
Sympatric species share identical geographical spaces, climatic conditions and survival pressures. Comparative chloroplast genomes among Anna and Lysionotus sympatric species enable exploration of genome-wide evolutionary dynamics of sympatric species. In this study, we assembled and annotated 10 complete chloroplast genomes, representing sympatric species distributed along the Sino-Vietnamese border. We conducted a comparison of chloroplast genomes, characterized their adaptive evolution and used multiple methods to clarify their phylogenetic relationships. Key findings included the following: 1. The number of CDs, rRNA and tRNA varied among different species, whereas they were relatively conserved between the two genera; 2. psaB-psaA, trnL-UAG and ndhD-psaC were identified as potential molecular markers for Anna species, with clpP and ycf1 proposed as effective molecular markers for Lysionotus species; 3. the types of simple sequence repeats (SSRs) and large sequence repeats (LRSs) showed a higher conservation in Lysionotus compared with Anna; 4. the codon usage preferences of the two genera showed convergent evolutionary trends and natural selection played a dominant role, with ycf1 and atpH being confirmed as significantly positively selected genes; 6. phylogenetic analyses using multiple approaches (ML, BI and NJ) consistently verified that Anna and Lysionotus each formed a well-supported monophyletic group. This study offers molecular insights into adaptation and differentiation patterns among distinct plant genera inhabiting the same extreme habitat.
Patients aged ≥ 70 years with relapsed/refractory multiple myeloma (RRMM) face unique challenges due to physiological changes and increased toxicity from treatments. Daratumumab-based regimens have shown efficacy, but direct comparisons in elderly populations are lacking. A multicenter retrospective study compared daratumumab, pomalidomide, and dexamethasone (DPd) to daratumumab, carfilzomib, and dexamethasone (DKd) in patients with RRMM aged ≥ 70 years. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and response rates. The study included 150 patients (119 DPd, 31 DKd). Baseline characteristics were similar, but DPd had more lenalidomide-refractory patients (90% vs. 74%, p = 0.035). Overall response rates were comparable (DPd 77%, DKd 74.5%, p = 0.8), but DKd had a significantly higher rate of deep responses (64.5% vs. 36%, p < 0.01). Median PFS was 12 months for DPd and 13 months for DKd (p = 0.6); median OS was 50 months for DPd and 28 months for DKd (p = 0.2). Multivariate analysis identified poor performance status and high-risk cytogenetics as adverse prognostic factors. DPd and DKd showed similar efficacy for elderly RRMM patients, with DKd achieving deeper responses. Treatment decisions should consider individual patient factors rather than focusing solely on efficacy differences.
Aardwolf (Proteles cristatus) is one of the four extant hyenas. Up to now, chromosome analysis of the aardwolf is limited to the knowledge that this insectivorous hyena shares the same 2n = 40 diploid chromosome number with the three bone-crushing hyena species. Here we present a detailed conventional banding and molecular cytogenetic characterization of the aardwolf karyotype. A chromosome-by-chromosome comparison with the spotted hyena (Crocuta crocuta) shows extensive conservation of chromosome size, morphology, and banding patters between the two hyenas. Karyotype conservation in hyenas is further supported by cat-aardwolf Zoo-FISH revealing almost identical patterns with previously available cat-spotted hyena Zoo-FISH, as well as extensive conserved synteny between cats and hyenas. Notably, hyena Chr12 and cat E1 share conserved synteny and carry the single nucleolus organizer region in both groups of species. Telomere-FISH in aardwolf and cat revealed only canonical telomeres and no interstitial sites, thus consistent with the overall karyotype conservation. However, there are also differences between aardwolf and spotted hyena Chr15, Chr16, and Chr19 due to heterochromatic additions in the aardwolf. Of these, the metacentric aardwolf Chr16 serves as a genomic feature that distinguishes this species from the spotted hyena in which the homeologous chromosome is acrocentric. In conclusion, improved cytogenetic and molecular characterization of the aardwolf karyotype expands the comparative knowledge about mammalian karyotypes and chromosome evolution, supports karyotypic conservation in feliform carnivores, and facilitates the construction of a high-quality chromosome-level annotated genome assemblies for the aardwolf and other hyenas.
Accurate molecular classification is essential for diagnosis, risk stratification, and treatment selection in B-cell lymphoblastic leukemia (B-ALL). In this study, we performed a comprehensive, real-world reclassification of 1015 consecutively diagnosed B-ALL patients using the fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) and the International Consensus Classification (ICC). An integrative genomic strategy that combined whole transcriptome sequencing, fusion detection, mutational analysis, and cytogenetics enabled reclassification according to both the WHO-HAEM5 and ICC frameworks, thereby substantially reducing the proportion of unclassifiable B-ALL from 41.9% (2016 WHO revision [WHO-HAEM4R]) to 15.9% (WHO-HAEM5) and 11.9% (ICC). Distinct clinical and prognostic features were identified across newly defined subtypes. Multivariable analysis confirmed that this genomic classification is a robust, independent predictor of survival after adjusting for age, minimal residual disease status, and transplant intervention. Specifically, HLF-rearranged and MEF2D-rearranged B-ALL conferred a persistently poor prognosis across all age groups despite allogeneic hematopoietic stem cell transplantation, highlighting an urgent need for novel therapeutic strategies. Gene expression profiling resolved cryptic subtypes, including ETV6::RUNX1-like, ZNF384-rearranged-like, and BCR::ABL1-like B-ALL, and uncovered diagnostic ambiguity in patients with concurrent lesions. In addition, we report emerging high-risk groups, including IDH1/2- and ZEB2 Q1072-mutated B-ALL, that may warrant recognition as distinct molecular entities. Our findings demonstrate the clinical use of integrative transcriptomic profiling in refining B-ALL taxonomy in guiding risk-adapted therapies and informing future revisions of diagnostic standards. This study supports the incorporation of high-throughput molecular diagnostics into routine leukemia classification and precision treatment planning.
Supernumerary B chromosomes have been identified in hundreds of species across many different taxa, each with their own evolutionary history, unique sequence composition, and epigenetic profile. In this study, we generated a detailed repetitive sequence and epigenetic landscape of the B chromosomes in Drosophila melanogaster. By comparing the repetitive DNA content of stocks with (+B) and without (0B) B chromosomes, we found nine satellite DNA (satDNA) sequences that were enriched in the +B genome, three of which were cytogenetically confirmed to be on the B chromosomes. Our satDNA analysis also led to the discovery of three novel satDNA repeats that are not on the B chromosomes and have not been described previously (Sat-307, Sat-597, and Sat-228). Analysis of transposable elements (TEs) revealed that although TEs comprise similar proportions of the 0B and +B genomes, the centromeric transposon G2/Jockey is modestly enriched in the +B genome, consistent with the high number of centromeres present in the +B genome. We also immunostained both male somatic and germline tissues to gain insight into the epigenetic state of the B chromosomes and found the presence of heterochromatin-associated histone modifications (H3K9me1, H3K9me2), a lack of acetylation (H4K5ac), and the absence of RNA polymerase II in the B chromosome nuclear territory, suggesting the B chromosomes have a reduced level of transcription. Together, our work further defines the genetic composition of the D. melanogaster B chromosome and establishes its epigenetic profile, which will provide a foundation for future work investigating changes to repetitive DNA over time and how a transcriptionally repressed chromosome influences chromatin maintenance in the genome.
BACKGROUND: Therapy-related acute lymphoblastic leukemia (t-ALL) is an aggressive subtype of ALL that arises after cytotoxic therapy. It is associated with adverse cytogenetics and older age, but survival outcomes compared with de novo ALL remain uncertain. We aimed to systematically evaluate survival differences in adults with t-ALL versus d-ALL. METHODS: We performed a systematic review and meta-analysis according to PRISMA guidelines. PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library were searched to Dec 31, 2024. Eligible studies included adults (≥ 18 years) with t-ALL or de novo ALL reporting survival. Pediatric studies, case reports, reviews, and abstracts were excluded. Two reviewers independently screened and extracted data. Quality was assessed with the MASTER scale. Hazard ratios (HRs) for overall survival were pooled using Doi’s quality effects model. The protocol was registered with PROSPERO (CRD42025625294). RESULTS: From 3,325 records, 27 retrospective cohort studies (169,237 patients; 1,827 with t-ALL) were included. Nine studies (30,527 patients) were eligible for meta-analysis. The pooled HR for mortality in t-ALL versus d-ALL was 1.07 (95% CI 0.94–1.23), showing no significant survival difference. Median survival ranged from 6 to 32 months in t-ALL and 11–50.6 months in d-ALL. Poor-risk cytogenetics were more frequent in t-ALL (43–100% vs. 31–66%), with higher TP53 mutations (38% vs. 10%) and complex karyotypes. Complete remission was lower in t-ALL (60–88.9% vs. 81.5–93%). Heterogeneity was moderate (I²=50.5%) with evidence of small-study effects. CONCLUSION: Despite adverse biology, t-ALL demonstrates survival comparable to d-ALL with modern therapies, particularly allogeneic transplantation.
In this study, we examined Y chromosome morphology in three species: European bison (Bison bonasus), American bison (Bison bison), and domestic cattle (Bos taurus). Peripheral blood lymphocytes were cultured, and C-banded metaphase preparations were analyzed to measure key Y chromosome parameters-absolute and relative length, absolute and relative area, and heterochromatin (C-band) content-using ImageJ software (ver. 1.54p). All traits deviated from normality (Shapiro-Wilk, p < 0.05). Non-parametric analyses revealed significant interspecific differences, with the strongest effects observed for C-band, followed by absolute and relative length. Principal Component Analysis (PCA) indicated a two-class structure, where domestic cattle formed a distinct cluster, while European and American bison grouped closely but remained separable. Linear Discriminant Analysis (LDA) achieved high classification accuracy (0.94), with misclassifications limited to American versus European bison. Generalized Linear Model (GLM) analyses further confirmed a strong species effect on C-band content (R2 = 0.916). These results identify the C-band as the most powerful discriminant, providing robust morphological differentiation among the three species and demonstrating the value of Y chromosome morphometry for comparative cytogenetic studies. Due to the limited sample size of American bison (n = 2), interpretations for this species should be made with caution.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). However, comparative effectiveness across CAR products, target antigens, and patient subgroups remains incompletely characterized. Particularly, with the emergence of G protein-coupled receptor family C group 5 member D (GPRC5D)-directed, bispecific, and dual-target strategies, efficacy in patients who have relapsed/refractory disease after anti-B cell maturation antigen (BCMA) therapy has not been studied in detail. We systematically searched 5 electronic databases from January 1, 2010 to December 5, 2025. Eligible studies reported clinical outcomes of CAR T-cell therapy in MM. Primary efficacy endpoints included overall response (ORR) and complete response (CR) rate. Safety endpoints included hematologic and immunologic toxicities. Random-effects meta-analyses were performed using R, with prespecified subgroup and meta-regression analyses according to demographic, disease and treatment-related factors such as antigen target, CAR construct, prior treatment burden, extramedullary disease and high-risk cytogenetics. Of 52 reports of 44 cohorts (2 frontline and 42 relapsed/refractory cohorts) including 1833 patients were analyzed. Across all CAR T-cell platforms, the pooled ORR was 88% (95% confidence interval [CI]: 83 to 91) and CR rate was 55% (95% CI: 47 to 62). For autologous BCMA-directed CAR T-cell therapy, ORR was 89% (95% CI: 82 to 93) and CR rate was 57% (95% CI: 47 to 66), whereas allogeneic BCMA CAR-T had a lower ORR of 58% (95% CI: 1 to 100) and CR rate of 21% (95% CI: 6 to 51). Bispecific and dual-target strategies demonstrated encouraging activity with BCMA/CD19-directed CAR T-cells achieving an ORR of 92% (95% CI: 89 to 95) and CR rate of 64% (95% CI: 16 to 94), while BCMA/CD38-directed CAR T-cells achieved an ORR of 88% (95% CI: 82 to 93) and CR rate of 61% (95% CI: 22 to 90). For GPRC5D-directed CAR T-cell therapy, ORR was 89% (95% CI: 84 to 92) and CR rate was 50% (95% CI: 32 to 69). Among BCMA-relapsed/refractory patients, subsequent GPRC5D-directed CAR T-cell therapy achieved an ORR of 82% (95% CI: 66 to 91) and CR rate of 35%. MRD negativity was observed in 78% (95% CI: 68 to 86) of evaluable patients overall. Subgroup analyses demonstrated significantly lower ORR and CR in cohorts with higher extramedullary disease. Grade ≥3 hematologic toxicities were frequent: neutropenia occurred in 83% (95% CI: 76 to 89), leukopenia in 73% (95% CI: 59 to 83), anemia in 46% (95% CI: 38 to 54), and thrombocytopenia in 48% (95% CI: 41 to 56). Grade ≥3 cytokine release syndrome occurred in 8% (95% CI: 6 to 11), while grade ≥3 immune effector cell-associated neurotoxicity syndrome occurred in 3% (95% CI: 2 to 5). CAR T-cell therapy produces high response rates, substantial depth of remission, and frequent MRD negativity in multiple myeloma, including heavily pretreated RRMM. Antigen switching strategies after anti-BCMA failure with GPRC5D-directed strategies appear promising. Bispecific and dual-target CAR T-cell strategies appear especially promising, with high response rates and deep remissions. Extramedullary disease and high prior treatment burden remain important poor prognostic factors. However, these findings remain largely derived from early-phase, single-arm studies, and prospective comparative trials are needed to further guide optimal choice of CAR-T and long-term efficacy.
Suleiman–El-Hattab syndrome (SULEHS; OMIM #618674) is an ultra-rare autosomal recessive multisystem neurodevelopmental disorder caused by biallelic loss-of-function variants in TASP1, with a characteristic combination of global developmental delay/intellectual disability, distinctive craniofacial dysmorphism, recurrent infections, congenital anomalies, and a typically cheerful affect. Because fewer than ten molecularly confirmed individuals have been reported, the phenotypic spectrum and neuroradiologic variability remain incompletely defined. We describe the first genetically confirmed Iranian patient with a clinical phenotype suggestive of SULEHS, including microcephaly, failure to thrive, syndromic facial features, neurodevelopmental delay (NDD), recurrent pneumonias, cardiac and genitourinary anomalies, hearing impairment, seizures, and a happy demeanor with drooling. Brain MRI demonstrated ventriculomegaly and a posterior fossa malformation consistent with a Dandy–Walker variant. Conventional cytogenetics and array-CGH were uninformative; therefore, whole-exome sequencing (WES) with segregation analysis was performed. In parallel, we conducted a targeted literature review and systematically compared our patient’s clinical and imaging findings with eight previously reported molecularly confirmed cases. WES identified a novel homozygous TASP1 variant (NM_017714.3:c.358 A > G; p.Met120Val), classified as a variant of uncertain significance (VUS), with both parents confirmed as heterozygous carriers. Comparative analysis across the eight published cases and our patient demonstrated substantial overlap in core features—microcephaly, failure to thrive, typical craniofacial gestalt (e.g., thick highly arched eyebrows with synophrys, hypertelorism, periorbital fullness, ear anomalies), recurrent respiratory infections, cardiovascular anomalies, developmental delay/intellectual disability (DD/ID), happy demeanor, and drooling—while several commonly reported findings (e.g., epicanthus, thick eyelids, thick lower lip vermilion, lumbosacral hirsutism, feeding difficulties, hypotonia) were absent in our patient. Neuroimaging across prior cases included corpus callosum abnormalities, ventriculomegaly, encephalomalacia, and posterior fossa malformations; in our case, only ventriculomegaly and posterior fossa malformation were present. This report expands the geographic and clinical spectrum of SULEHS by documenting the ninth reported molecularly confirmed case and the first from Iran, and it further delineates phenotypic and neuroradiologic heterogeneity by showing ventriculomegaly with a posterior fossa malformation consistent with a Dandy–Walker variant. In our patient, conventional genetic testing (karyotype and array-CGH) was uninformative, whereas WES identified a novel homozygous TASP1 classified as VUS with parental carrier segregation; although functional validation is still required, the strong phenotype–genotype concordance supports its likely contribution and underscores the diagnostic value of comprehensive genomic testing in undiagnosed neurodevelopmental syndromes.