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Minimal residual disease (MRD) based risk stratification criteria for specific genetic subtypes remained unclear in childhood acute lymphoblastic leukemia (ALL). Among 723 children with newly diagnosed ALL treated with the Chinese Children Leukemia Group CCLG-2008 protocol, MRD was assessed at time point 1 (TP1, at the end of induction) and TP2 (before consolidation treatment) and the MRD levels significantly differed in patients with different fusion genes or immunophenotypes (P all < 0.001). Moreover, the prognostic impact of MRD varied by distinct molecular subtypes. We stratified patients in each molecular subtype into two MRD groups based on the results. For patients carrying BCR::ABL1 or KMT2A rearrangements, we classified patients with MRD < 10–2 at both TP1 and TP2 as the low MRD group and the others as the high MRD group. ETV6::RUNX1+ patients with TP1 MRD < 10–3 and TP2 MRD-negative were classified as the low MRD group and the others as the high MRD group. For T-ALL, We defined children with TP1 MRD ≥ 10–3 as the high MRD group and the others as the low MRD group. The 10-year relapse-free survival of low MRD group was significantly better than that of high MRD group. We verified the prognostic impact of the subtype-specific MRD-based stratification in patients treated with the BCH-ALL2003 protocol. In conclusion, the subtype-specific MRD risk stratification may contribute to the precise treatment of childhood ALL. [ABSTRACT FROM AUTHOR]

Low expression of CTBP2 and CASP8AP2 correlated with poor outcome and predicted risk of relapse in pediatric B-cell acute lymphoblastic leukemia (B-ALL). This study aimed to investigate the molecular mechanism by which CASP8AP2 regulates LEF1 expression by interacting with CtBP2 and ZEB2 in Acute lymphoblastic lymphoma (ALL). There was an interaction between CASP8AP2, ZEB2, and CtBP2, and then the interaction between CtBP2 and ZEB2 was observed after downregulating the expression of CASP8AP2. The wild type (containing the ZEB2 binding site) or mutant (containing a mutant binding site) LEF1 gene promoter sequence was inserted into the pGL3-basic plasmid, and a dual-luciferase reporter gene detection system was used to observe how CASP8AP2, ZEB2, and CtBP2 regulate the transcription of the LEF1 gene. We conclude that CASP8AP2, CtBP2, and ZEB2 can all bind to the LEF1 gene promoter region and reduce the luciferase activity of the LEF1 promoter. Meanwhile, the interaction of ZEB2 and the LEF1 promoter was significantly weakened after downregulation of CASP8AP2. Knockdown of CASP8AP2 in the 697 cell lines resulted in the significant upregulation of the mRNA expression levels of the stemness-related genes CD44, JAG1, and SALL4. In conclusion, CASP8AP2 is vital for the interaction between CtBP2 and ZEB2, inhibiting LEF1 and stemness-related genes expression ALL. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2033369. [ABSTRACT FROM AUTHOR]

Introduction: Relapse remained the major obstacle to improving the prognosis of children with acute lymphoblastic leukemia (ALL). This study aimed to investigate the changing patterns of Ig/TCR gene rearrangements between diagnosis and relapse and the clinical relevance and to explore the mechanism of leukemic relapse. Methods: Clonal Ig/TCR gene rearrangements were screened by multiplex PCR amplification in 85 paired diagnostic and relapse bone marrow (BM) samples from children with ALL. The new rearrangements presented at relapse were quantitatively assessed by the RQ‐PCR approach targeting the patient‐specific junctional region sequence in 19 diagnostic samples. The relapse clones were further back‐traced to diagnostic and follow‐up BM samples from 12 patients. Results: Comparison of Ig/TCR gene rearrangements between diagnosis and relapse showed that 40 (57.1%) B‐ALL and 5 (33.3%) T‐ALL patients exhibited a change from diagnosis to relapse, and 25 (35.7%) B‐ALL patients acquired new rearrangements at relapse. The new relapse rearrangements were present in 15 of the 19 (78.9%) diagnostic samples as shown by RQ‐PCR, with a median level of 5.26 × 10−2. The levels of minor rearrangements correlated with B immunophenotype, WBC counts, age at diagnosis, and recurrence time. Furthermore, back‐tracing rearrangements in 12 patients identified three patterns of relapse clone dynamics, which suggested the recurrence mechanisms not only through clonal selection of pre‐existing subclones but also through an ongoing clonal evolution during remission and relapse. Conclusion: Backtracking Ig/TCR gene rearrangements in relapse clones of pediatric ALL revealed complex patterns of clonal selection and evolution for leukemic relapse. [ABSTRACT FROM AUTHOR]

Background: The flotillin family member flotillin-1 (FLOT1) encodes a caveolae-associated, integral membrane protein that belongs to lipid raft family and involves in vesicular trafficking and signal transduction. However, the role of FLOT1 in development and progression of cancer remains largely unknown. The present study was aimed to investigate the clinical and prognostic significance of FLOT1 in hepatocellular carcinoma (HCC). Methods: Real-time PCR and western blot analyses were applied to examine FLOT1 expression in fourteen HCC cell lines and one normal hepatic cell line, ten pairs of primary HCC and matched adjacent noncancerous liver tissues from the same patient. Immunohistochemistry (IHC) was performed to examine FLOT1 protein expression in paraffin-embedded tissues from 196 HCC patients. Statistical analyses were applied to evaluate the diagnostic value and associations of FLOT1 expression with clinical parameters. Results: FLOT1 expression was evidently up-regulated in HCC tissues compared with that in the matched adjacent noncancerous liver tissues. In the 196 cases of tested HCC samples, FLOT1 protein level was positively correlated with Tumor size (P = 0.025), clinical stage (P<0.002), CLIP stage (P<0.001), vascular invasion (P<0.001), relapse (P<0.001), and serum AFP levels (P = 0.025). Patients with higher FLOT1 expression had shorter overall survival time, whereas those with lower FLOT1 expression had longer survival time. Conclusions: Our study demonstrated FLOT1 is associated with aggressive characteristics of HCC, and suggested the possibility of its use as a prognostic marker in patients with HCC. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the combined impact of IKZF1 deletions/high expression of CRLF2 on the prognosis of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). IKZF1 deletions and CRLF2 expression were assessed in bone marrow samples from 117 children with newly diagnosed BCP-ALL. Sixteen (13.7%) patients were found to harbor IKZF1 deletions, which was associated with inferior outcomes. The event-free survival (EFS) for patients with high -CRLF2 expression was significantly worse than that for low -CRLF2 expression. Moreover, combined modeling of IKZF1+/CRLF2high identified 7.8% of cases as the highest risk subgroup (7-year EFS 33.3 ± 15.7%). In a multivariate analysis, IKZF1+/CRLF2high remained a strong independent prognostic factor for EFS (HR: 14.263, p = 0.019). IKZF1 deletions and high -CRLF2 expression were associated with inferior outcomes, and the coexistence of IKZF1+/CRLF2high had a significant impact on an integrated prognostic model for high-risk BCP-ALL. [ABSTRACT FROM AUTHOR]

CtBP is a known corepressor abundantly expressed in cancer and regulates genes involved in cancer initiation, progression, and metastasis. This study aimed to investigate the prognostic significance of CTBP2 expression in a cohort of pediatric patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL). It further evaluated the role of combined CTBP2 and CASP8AP2 expression in risk of relapse of BCP-ALL. The expression of CTBP2 mRNA was retrospectively detected by a qRT-PCR approach in bone marrow samples from 104 children with newly diagnosed BCP-ALL. CASP8AP2 was assessed simultaneously in the 100 patients included in this study. The receiver operating characteristic (ROC) curve analysis determined the cut off levels for CTBP2 and CASP8AP2 expression with good predictive significance for relapse of BCP-ALL. Patients with low CTBP2 expression had inferior relapse-free survival (RFS) and event-free survival (EFS) when compared to patients with high-CTBP2 expression. The expression level of CTBP2 was significantly associated with CASP8AP2 expression (r = 0.449, P < 0.001). Patients were stratified into three groups according to the combined evaluation of the two gene expression, and patients with simultaneous low-expression had the worst outcome (6-year RFS: 64.6%±12.8%, P < 0.001). Multivariate analysis demonstrated the expression of CTBP2 and CASP8AP2, minimal residual disease (MRD) at day 33 remained as independent prognostic factors for RFS. Based on the final Cox hazards model, we proposed an algorithm to calculate the risk index, which was more precise for predicting relapse. In conclusion, low expression of CTBP2 and CASP8AP2 correlated with poor outcome and predicted risk of relapse in pediatric BCP-ALL. [ABSTRACT FROM AUTHOR]

Background: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm. A few LCH patients had Macrophage activation syndrome-hemophagocytic lymphohistiocytosis (MAS-HLH), a life-threatening, hyper-inflammatory syndrome. We retrospectively described the clinical-biological characteristics of a series of 28 pediatric LCH patients with MAS-HLH in a single center. We further analyzed the difference in treatment outcomes between second-line chemotherapy (cytarabine and cladribine) and targeted therapy (dabrafenib) for BRAF-V600E-positive patients.Results: LCH patients with MAS-HLH were aged < 2 years, harbored high frequencies of risk organ, skin, or lymph nodes involvement, and most of them carried BRAF-V600E mutation in lesions (88.0%) or plasma (90.5%). Patients were firstly treated with the initial induction first-line therapy (vindesine-steroid combination), and most of them (26/28) failed to control the active MAS-HLH after one six-week course of induction treatment. Then they were shifted to second-line chemotherapy or targeted therapy dabrafenib. BRAF-V600E-mutant patients treated with dabrafenib had prompt resolution of MAS-HLH signs and symptoms with less toxicity than second-line chemotherapy. Moreover, the progression-free survival (PFS) rate for patients given dabrafenib was much higher than those treated with chemotherapy (4 year-PFS: 75% vs. 14.6%, P = 0.034).Conclusions: LCH patients with MAS-HLH harbored specific clinical-biology characteristics compared to the multisystem LCH without MAS-HLH. The BRAF inhibitor dabrafenib provides a promising treatment option for LCH with MAS-HLH. [ABSTRACT FROM AUTHOR]

To characterize the genetic profiles and relationships between ancient ethnic populations, we analyzed polymorphisms in mitochondrial DNA (mtDNA) isolated from the blood of 753 members of 12 ethnic groups (Buyi, Dong, Gelao, Hui, Man, Miao, Menggu, Mulao, Maonan, Qiang, She and Zhuang) living in the Guizhou Province of China. The 9-bp deletion of mtDNA was detected by the polymerase chain reaction (PCR) and PCR-PAGE, and 11 SNPs by restriction fragment length polymorphism and mini-sequencing. Thereafter, these genotyping results were verified by PCR-DNA sequencing. The mtDNA of these populations exhibited considerable diversity, both with respect to the haplogroups M and N, and subgroups thereof. The differences between the major ethnic groups reflected the maternal inheritance. These ethnic groups in Guizhou demonstrated a genetic profile that differed considerably from that of other Asian populations. Our findings indicate that the matrilineal genetic profiles of Guizhou groups are relatively complex and distinct, showing relationships that reflect national history and geography. [ABSTRACT FROM AUTHOR]