Volume 03 · Issue 03 · 2021

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that frequently occurs in children and adolescents, which results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation of T-ALL lymphoblasts are sustained by activation of strong oncogenic drivers. Mounting evidence highlights the critical role of the NOTCH1-MYC highway toward the initiation and progression of T-ALL. MYC has been emphasized as a primary NOTCH1 transcriptional target impinging in leukemia-initiating cell activity particularly responsible for disease onset and relapse. These findings lay a foundation of T-ALL as an ideal disease model for studying MYC-mediated cancer. The biology of MYC deregulation in T-ALL supports innovative strategies for therapeutic targeting of MYC. To summarize the relevant literature and data in recent years, we here provide a comprehensive overview of the functional importance of MYC in T-ALL development, and the molecular mechanisms underlying MYC deregulation in T-ALL. Finally, we illustrate the innovative MYC-targeted approaches that have been evaluated in pre-clinical models and shown significant efficacy. Given the complexity of T-ALL molecular pathogenesis, we propose that a combination of anti-MYC strategies with conventional chemotherapies or other targeted/immunotherapies may provide the most durable response, especially for those patients with relapsed and refractory T-ALL.

Fanconi anemia (FA), an X-linked genetic or autosomal recessive disease, exhibits complicated pathogenesis. Previously, we detected the mutated Dynein Axonemal Heavy Chain 2 (DNAH2) gene in 2 FA cases. Herein, we further investigated the potential association between DNAH2 and the homologous recombination repair pathway of FA. The assays of homologous recombination repair, mitomycin C (MMC) sensitivity, immunofluorescence, and ubiquitination modification were performed in U2OS and DR-U2OS cell lines. In MMC-treated U2OS cells, the downregulation of the DNAH2 gene increased the sensitivity of cells to DNA inter-strand crosslinks. We also observed the reduced enrichment of FANCD2 protein to DNA damage sites. Furthermore, the ubiquitination modification level of FANCD2 was influenced by the deficiency of DNAH2. Thus, our results suggest that DNAH2 may modulate the cell homologous recombination repair partially by increasing the ubiquitination and the enrichment to DNA damage sites of FANCD2. DNAH2 may act as a novel co-pathogenic gene of FA patients.

Fluorescence in situ hybridization (FISH) evaluation is essential for initial risk stratification in multiple myeloma (MM). The presence of specific cytogenetic abnormalities (CA) confers a heterogeneity impact on prognosis. However, the cutoff values among different centers are not uniform. Therefore, we conduct this study to better predict the prognosis of newly diagnosed MM patients based on FISH results. The Kaps method was used to calculate the chromosomal abnormal cutoff values. A total of 533 participants were included in the study. The best cutoff value of overall survival were as follows: 17p-20.1 %, 13q-85%, 1q21 + 39%, t(11;14) 55.5%, t(14;16) 87%, and t(4;14) 53.5%. The survival analysis showed that 17p-and 1q21 + were the independent factors affecting both OS and progress free survival (PFS) among CA. The analysis based on the cutoff value obtained by Kaps suggested that 13q-, t(14;16), 17p-, and 1q21 + were independent factors affecting OS among CA; t(14;16), 17p-, and 1q21 + were independent factors affecting PFS among CA. The prognostic model was constructed by the Kaps method with the Harrell concordance index (c-index) at 0.719 (95% CI, 0.683-0.756; corrected 0.707), which was higher than that calculated by the European Myeloma Network criteria (0.714; 95% CI, 0.678-0.751; corrected 0.696). In conclusion, chromosomal abnormalities in different proportions and combinations can affect the prognosis of MM patients. Therefore, effective criteria should be formulated to evaluate the prognosis of MM patients better.

Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in a variety of myeloid disorders. Although CSF3R point mutations (eg, T618I) are emerging as key players in chronic neutrophilic leukemia/atypical chronic myelogenous leukemia , the significance of rarer CSF3R mutations is unknown. Here, we report a 32-year-old female who was diagnosed as Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) with the CSF3R M696T mutation and was undergone unrelated donor hematopoietic stem cell transplantation. The patient achieved complete remission with chemotherapy in combination with tyrosine kinase inhibitor (TKI) and long-term survival by unrelated donor transplantation. Meanwhile, we performed a series of experiments using murine interleukin 3 (IL-3)-dependent Ba/F3 cell line to evaluate the transforming capacity of the CSF3R M696T mutation. We confirmed the presence of a CSF3R M696T germline mutation in this patient which was inherited from her mother. The in vitro experiment results showed that the CSF3R M696T mutation contributes marginally to the tumor transformation of Ba/F3 cells, indicating that CSF3R M696T mutation was neutral in tumor transformation ability. We concluded that TKI is effective in patients with the CSF3R M696T mutation in Ph⁺ ALL and donors with CSF3R M696T mutation might still be selected as the candidate for transplantation.