Childhood B Acute Lymphoblastic Leukemia

In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.

Moreover, several aberrant markers, such as CD2, CD56, CD7, and CD117, were rarely expressed in the B-ALL samples, and if expressed, they were enriched in specific genetic subtypes. The results of this study indicate that immunophenotypic features are correlated with specific genetic subtypes of childhood B-ALL.

Finally, we found that germline NBN variant carriers, all of which were identified as heterozygous genotypes, showed similar survival outcomes relative to those with WT status. Taken together, our findings provide novel insights into the genetic predisposition to B-ALL, and the impact of NBN variants on protein function and suggest that heterozygous NBN variant carriers may safely receive B-ALL therapy.

Further functional characterization using the CRISPR-Cas13d system demonstrated that circBARD1, overexpressed in TCF3::PBX1 patients and regulated by NUDT21, might be involved in leukemogenesis through the activation of p38 via hsa-miR-153-5p. Our results suggest that circRNAs could play a role in the pathogenesis of childhood B-ALL.

As a result, Ryan et al. endorsed the routine use of WGS to discover more abnormalities of clinical significance that define new genetic subtypes, as well as to improve diagnosis, risk stratification, and therapy.

In conclusion, our results indicated a critical role for aberrant cytokine expression profiles in the progression of childhood B-ALL. Distinct cytokine subgroups with different clinical features and immune response have been identified in patients with B-ALL at the time of diagnosis.

Despite having the MEF2D-HNRNPUL1 fusion gene, the prognosis was favorable. Improved diagnostic genomic testing will enable future prospective studies to clarify the clinical significance of the ZNF384 and MEF2D rearrangements in childhood and young adult BCP-ALL.

Alteration in the miRNA cargo of NK exosomes, together with their reduced cytotoxic activity, could represent another strategy exerted by cancer to evade the immune response. Our study provides new information on the molecular mechanisms used by NK exosomes to exert anti-tumor-activity and offers new clues to integrate cancer treatments with NK exosomes.

Further inhibition of glutaminolysis has a pronounced additive effect. Thereby, this study presents the basis for further investigations in the context of augmenting the efficacy of this critical arm of chemotherapy in cALL.

After CAR-T cells' administration, measurements at several timepoints accurately detect their proliferation intensity in vivo. The outcome of CAR-T cell therapy largely depends on biological characteristics of the tumors rather than on the immunophenotype of produced CAR-Ts.

Low expression of DNMT3A associates with poor prognosis in children with B-ALL. Knock-out of DNMT3A confers resistance to DNR on leukemic cells.

The SMYD2 gene plays a vital oncogenic role in childhood B-ALL. The association of high SMYD2 levels with unfavorable cytogenetics in childhood B-ALL may be helpful in understanding the relationship between structural chromosomal abnormalities and epigenetic dysregulation. High SMYD2 levels may be useful in the prediction of prognosis in childhood B-ALL.

Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates. Overall, we have validated that WGS provides a standalone, reliable genetic test to detect all subtype-defining genetic abnormalities in B-ALL, accurately classifying patients for the risk-directed treatment stratification, while simultaneously performing as a research tool to identify novel disease biomarkers.

Individuals with constitutional structural chromosome 21 rearrangements such as ring 21 require a close surveillance and long-term follow-up studies to establish their risk of B-ALL relapse and possibility of developing other malignancies. Germline analysis is recommended to all pediatric patients with iAMP21-related B-ALL to rule out structural chromosome 21 rearrangements and to elucidate molecular mechanisms of iAMP21 formation.

Conclusion Together, our study features NGS of the largest cohort of relapsed childhood ALL samples, identifies novel resistance markers for ETV6::RUNX subtype, and uncovers novel associations between resistance drivers and subtypes. These finding may shape future clinical management of childhood ALL.

We propose that our strategy represents a new standard of care for reinduction therapy in relapsed childhood B-ALL. DO and AV are joint senior authors

Instead, relapse-specific mutations occurred in multiple genetic loci often involved in resistance to either glucocorticoids or purine analogs (e.g., 6-mercaptopurine, or 6-MP). Therefore, inclusion of NT5C2 exon 4a phenocopies relapse-specific mutations and could serve as both a valuable predictive biomarker in B-ALL and potentially chronic myelogenous (CML) and acute myeloid leukemia (AML). Additionally, at least in vitro, expression of this non-canonical isoform conferred collateral sensitivity to the purine biosynthesis inhibitor Mizoribine, suggesting the existence of a therapeutic window to treat leukemias with dysregulated splicing.

S100A8 levels were compared in B-ALL and relapsed B-ALL lymphoblasts that were sensitive and resistant to Vincristine, respectively...According to the findings of the present study, S100A8 is effective in developing lymphoblast resistance to chemotherapy, and its enhanced expression may contribute to shifting B-ALL into the relapse phase of the illness. As a result, S100A8 may be a valuable target for managing and improving relapses B-ALL.

In conclusion, in our cohort, a high occurrence of CRLF2 abnormalities was documented, particularly the P2RY8-CRLF2 rearrangement, which might represent a characteristic of the Mexican population. Targeted therapy to treat this group of patients could improve OS.

Noteworthy, we observed higher CD38 expression on WBC than blasts in MRD > 0.1% patients. We suggest that NT5E gene and CD38 protein expression, of the ectonucleotidases family, could provide interesting prognostic biomarkers for childhood B-ALL.

Furthermore, we evaluated the cellular viability in REH, RS4;11, 697 and TOM-1 cell lines after exposure to iron as ferric ammonium citrate (FAC 100 to 400 µM), deferoxamine (DFO 25 µM) and FAC+DFO (100 µM + 25 µM), using MTT assay at 24-48 and 72h...TOM-1, REH and RS4;11 behave as resistant cell lines, whilst the 697 appear as not sensitive to iron metabolism. In conclusion, leukemia cell lines can be considered as trustable in vitro models for further studies in ALL to investigate whether iron metabolism can be determinant for survival and resistance, and consequently a target for treatment.

Collectively, we identified a pre-pubertal condition together with high CXCR4 expression as factors affecting the leukemia permissive testicular microenvironment. We propose CXCR4 as a promising target for therapeutic prevention of testicular relapses in childhood B-ALL.

For many cases of ALAL, experimental approaches indicate lineage aberrancy arises from acquisition of a founding genetic alteration into a hematopoietic stem or progenitor cell. Determination of optimal therapeutic approach requires genomic characterization of uniformly treated ALAL patients in prospective studies, but several approaches, including kinase inhibitors and BH3 mimetics may be efficacious in subsets of ALAL.

The unfavorable prognostic value of GAS5 overexpression was strongly validated in the high-risk/stem-cell transplantation subgroup. Finally, multivariate models incorporating GAS5 levels resulted in superior risk stratification and clinical benefit for chALL prognostication, supporting personalized prognosis and precision medicine decisions in chALL.

Conclusions These findings validate the presence of a unique monocyte subpopulation associated with childhood B-ALL and suggests that assessing this population in PB at diagnosis may be of prognostic significance. The availability of small molecule inhibitors and monoclonal antibodies targeting CSF1R-expressing monocytes may offer a novel approach to treating B-ALL.

In an ETV6-RUNX1+ (E6R1+) Cdkn2a-/- mouse model of B-ALL, decreased levels of IL-10 accelerated B cell neoplasms in a dose dependent manner, and altered the mutational profile of these neoplasms. Our results illuminate a mechanism through which a low level of IL-10 can create risk of leukemic transformation and support developing evidence that microbial dysbiosis contributes to pediatric B-ALL.

In MS2010, with vincristine at day 1, no day 8 poor PB response was observed in DUX4 subtype (P=0.03)...Compared to MS2003, outcome of PAX5alt B-ALL with IKZF1 co-deletion was improved by treatment intensification in MS2010 (5-year CIR 80.0% vs 0%; P=0.05). In conclusion, despite its poor initial response, DUX4 B-ALL had a favorable overall outcome, and the prognosis of PAX5alt was strongly dependent on IKZF1 co-deletion.

P2, N=94, Completed, St. Jude Children's Research Hospital | Active, not recruiting --> Completed

Our study represents a powerful conceptual framework for combinatorial drug discovery based on systematic interrogation of synergistic vulnerability pathways with pharmacologic inhibitor validation in preclinical human leukemia models.

Analyses of deletion breakpoint sequences are required to further understand the mutagenic effects of tobacco smoke in childhood ALL.

P2, N=94, Active, not recruiting, St. Jude Children's Research Hospital | Trial completion date: Apr 2021 --> Jul 2021 | Trial primary completion date: Apr 2021 --> Jul 2021

In Europe, tisagenlecleucel (Kymriah™) has a marketing authorization for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia in children and young adults and for the relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The marketing authorization for axicabtagene ciloleucel (Yescarta™) is the treatment of relapsed/refractory DLBCL and mediastinal B-cell lymphoma. Both products are "living drugs" and genetically modified autologous T cells directed against CD19 which is an antigen expressed throughout B lymphoid differentiation and on many B malignancies. This collaborative work - part of a series of expert works on the topic - aims to provide practical advice to assist collection facilities that procure the starting material i.e. blood mononuclear cells for autologous CAR T-cell manufacturing.

Based on the expression of tumor cell surface antigens(such as CD19, CD20 and CD22), the specific monoclonal antibodies, bispecific antibodies and chimeric antigen receptor T cells (CAR-T), and other targeted immunotherapy can greatly improve the efficacy of B-ALL patients, especially for patients with relapse and refractory. In this review, the progress of immunotherapy against B-ALL cell surface antigen is summarized briefly.

Values higher than 2.5 Specific fluorescence indices (SFIs) and 35% expression were sensitive predictors to induction failure. CD105 can be considered as a potential prognostic marker for the detection of response to induction therapy in childhood B-ALL, and it can serve to optimize treatment decisions.

CAR-T cells can effectively treat relapsed/refractory TCF3-HLF-positive childhood B-ALL with acceptable toxicity, which could be a new treatment option for this subtype compared with chemotherapy or HSCT.

Our data support the clinical utility of profiling CNAs to potentially refine current risk stratification strategies of patients with B-ALL.

In Europe, tisagenlecleucel (Kymriah) has a marketing authorization for the treatment of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia in children and young adults and of R/R diffuse large B-cell lymphoma (DLBCL). The marketing authorization for axicabtagene ciloleucel (Yescarta) is the treatment of DLBCL and primary R/R mediastinal B-cell lymphoma. The two products are autologous T-cells directed against CD19. This collaborative work, part of a series of expert opinion-based work, aims to give practical advice to help centers in selection of patients for commercially available CAR T-cell treatment.

Other genetic alterations including iAMP21, IKZF1 deletions, ERG deletions, PAX5, which have clinical significance or are associated with novel subtypes of ALL, were identified. In conclusion, appropriate application of MLPA aids the identifications of CNV and aneuploidy in childhood B-ALL.