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Nature Communications Jan 2024Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting...
Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph B-ALL patients. IL-17A promotes the progression of Ph B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph B-ALL progression and suggest potential therapeutic options for Ph B-ALL with Th17-enriched niches.
Topics: Humans; Imatinib Mesylate; Philadelphia Chromosome; Fusion Proteins, bcr-abl; Interleukin-17; Drug Resistance, Neoplasm; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Acute Disease
PubMed: 38172124
DOI: 10.1038/s41467-023-44270-3 -
International Journal of Biological... 2024Chronic myeloid leukemia (CML) is a malignant clonal disease involving hematopoietic stem cells that is characterized by myeloid cell proliferation in bone marrow and... (Review)
Review
Chronic myeloid leukemia (CML) is a malignant clonal disease involving hematopoietic stem cells that is characterized by myeloid cell proliferation in bone marrow and peripheral blood, and the presence of the Philadelphia (Ph) chromosome with BCR-ABL fusion gene. Treatment of CML has dramatically improved since the advent of tyrosine kinase inhibitors (TKI). However, there are a small subset of CML patients who develop resistance to TKI. Mutations in the ABL kinase domain (KD) are currently recognized as the leading cause of TKI resistance in CML. In this review, we discuss the concept of resistance and summarize recent advances exploring the mechanisms underlying CML resistance. Overcoming TKI resistance appears to be the most successful approach to reduce the burden of leukemia and enhance cures for CML. Advances in new strategies to combat drug resistance may rapidly change the management of TKI-resistant CML and expand the prospects for available therapies.
Topics: Humans; Tyrosine Kinase Inhibitors; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Protein Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 38164178
DOI: 10.7150/ijbs.86305 -
Frequency and Prognostic Impact of Aberrant Antigens Expression among Egyptian Adult Acute Leukemia.Asian Pacific Journal of Cancer... Dec 2023Aberrant antigen expression was reported to be due to genetic and epigenetic dysregulation. This study aimed to address aberrant antigen expression and its link to poor...
OBJECTIVE
Aberrant antigen expression was reported to be due to genetic and epigenetic dysregulation. This study aimed to address aberrant antigen expression and its link to poor prognostic genetic markers in acute leukemia patients.
METHODS
This study included 432 newly diagnosed acute leukemia patients (AML, B-ALL). For all included patients blast cells expression for line assignment CD33 CD13 on B-All and CD7 on cytogenetically normal-AML blasts was assessed by flow cytometry in parallel to FLT3 and Philadelphia and philadelphia like chromosome in B-ALL.
RESULTS
From the total 432 cases of acute leukemia, the most frequent aberrant antigen expressed in B acute lymphoid leukemia (ALL) was CD33 (23.3%) followed by CD13(16.7%); while the most frequent one in AML was CD7 (16.7%). Aberrant myeloid phenotype in B-ALL was associated with lower mean total leukocytes count (TLC), low platelets count, positive Philadelphia like chromosome, shorter overall survival compared to the B-ALL without. Aberrant lymphoid phenotype (CD7) in AML was associated with a higher platelets count, FLT3 mutation, shorter disease-free and overall survival compared to those patients without.
CONCLUSION
CD7 aberrant antigen expression is frequently detected in patients with CN-AML and frequently associated with FLT3 mutation. While in patients with B-ALL the most frequently detected ones are CD33 and CD13 which are frequently associated with Philadelphia like chromosome.
Topics: Adult; Humans; Antigens, CD; Prognosis; Egypt; Leukemia, Myeloid, Acute; Antigens, CD7; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Immunophenotyping
PubMed: 38156867
DOI: 10.31557/APJCP.2023.24.12.4301 -
Blood Cell Therapy Aug 2023The most important prognostic factor for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is minimal residual disease (MRD). Previous studies have...
The most important prognostic factor for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is minimal residual disease (MRD). Previous studies have reported copy number variants of genes such as , , and . These gene mutations can be analyzed using multiplex ligation-dependent probe amplification (MLPA), which is less costly and easier to perform than large-scale gene mutation analyses. In this study, we performed copy number variant analysis of leukemia cells at the first onset of Ph+ALL in a case series of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using the MLPA method. We analyzed how it influenced allo-HSCT prognosis together with MRD information. copy number variations significantly increased the rate of post-transplant recurrence (P=0.025) and significantly reduced disease-free survival (P=0.015). Additionally, patients with deletions had a significantly higher post-transplant recurrence rate (P=0.042). Although they were positive for pre-transplant MRD, no relapse was observed in patients with wild-type copy number variations in or . copy number variation is a crucial factor that can be confirmed at initial onset as a post-transplant prognostic factor of Ph+ALL.
PubMed: 38146355
DOI: 10.31547/bct-2023-004 -
Cureus Nov 2023Chronic myeloid leukemia (CML) with BCR-ABL1-positive cells is a myeloproliferative neoplasm (MPN) characterized by a chromosomal translocation t(9,22)(q34.1;q11.2),...
Bi-lineage B- and T-lymphoid Extramedullary Blast Crisis at an Initial Presentation of Chronic Myeloid Leukemia: A Case Report and Literature Review of Extramedullary Blast Crisis.
Chronic myeloid leukemia (CML) with BCR-ABL1-positive cells is a myeloproliferative neoplasm (MPN) characterized by a chromosomal translocation t(9,22)(q34.1;q11.2), which results in the formation of a Philadelphia (Ph) chromosome containing the BCR-ABL1 fusion gene. Extramedullary blast crisis (EBC) associated with bcr/abl-positive CML is a rare initial presentation. Here, we present and discuss the case of a 51-year-old man who presented with a weight loss history, cervical swelling, and left-sided abdominal pain. He had a white blood cell count of 147,910/mm3. The blood smear study revealed myelemia in 23% and 8% of blast-like cells. The bone marrow aspiration and biopsy showed a richly cellularized sample; the megakaryocytes were present; the granular neutrophil line was at 89% with blasts at 1%. The cytogenetic analysis revealed a complex karyotype with the presence of a Philadelphia chromosome t (9, 22) (q34, q11) associated with additional cytogenetic abnormalities (ACA). Molecular analysis (PCR) detected a BCR::ABL1 (p210) rearrangement. At this point, a diagnosis of CML in the chronic phase was confirmed, but a cervical lymph node biopsy analysis revealed a bi-phenotypic B/T-lymphoblastic lymphoma (LBL) and expressed at fluorescent in situ hybridization (FISH) analysis BCR::ABL1 rearrangement. These findings were consistent with the diagnosis of a bi-phenotypic B/T extramedullary blast crisis associated with CML.
PubMed: 38143593
DOI: 10.7759/cureus.49348 -
British Journal of Cancer Mar 2024Wilms tumor (WT) exhibits structural and epigenetic changes at chromosome 11p15, which also cause Beckwith-Wiedemann Syndrome (BWS). Children diagnosed with BWS have...
BACKGROUND
Wilms tumor (WT) exhibits structural and epigenetic changes at chromosome 11p15, which also cause Beckwith-Wiedemann Syndrome (BWS). Children diagnosed with BWS have increased risk for WT. The aim of this study is to identify the molecular signaling signatures in BWS driving these tumors.
METHODS
We performed whole exome sequencing, methylation array analysis, and gene expression analysis on BWS-WT samples. Our data were compared to publicly available nonBWS data. We categorized WT from BWS and nonBWS patients by assessment of 11p15 methylation status and defined 5 groups- control kidney, BWS-nontumor kidney, BWS-WT, normal-11p15 nonBWS-WT, altered-11p15 nonBWS-WT.
RESULTS
BWS-WT samples showed single nucleotide variants in BCORL1, ASXL1, ATM and AXL but absence of recurrent gene mutations associated with sporadic WT. We defined a narrow methylation range stratifying nonBWS-WT samples. BWS-WT and altered-11p15 nonBWS-WT showed enrichment of common and unique molecular signatures based on global differential methylation and gene expression analysis. CTNNB1 overexpression and broad range of interactions were seen in the BWS-WT interactome study.
CONCLUSION
While WT predisposition in BWS is well-established, as are 11p15 alterations in nonBWS-WT, this study focused on stratifying tumor genomics by 11p15 status. Further investigation of our findings may identify novel therapeutic targets in WT oncogenesis.
Topics: Child; Humans; Beckwith-Wiedemann Syndrome; DNA Methylation; Wilms Tumor; Genotype; Kidney Neoplasms
PubMed: 38142265
DOI: 10.1038/s41416-023-02538-x -
Cancers Dec 2023Recent studies have indicated that more than half of adult patients newly diagnosed with Ph+ ALL can now achieve a cure. However, determining the most suitable protocol... (Review)
Review
Recent studies have indicated that more than half of adult patients newly diagnosed with Ph+ ALL can now achieve a cure. However, determining the most suitable protocol for less-resourced settings can be challenging. In these situations, we must consider the potential for treatment toxicity and limited access to newer agents and alloSCT facilities. Currently, it is advisable to use less intensive induction regimens for Ph+ ALL. These regimens can achieve high rates of complete remission while causing fewer induction deaths. For consolidation therapy, chemotherapy should remain relatively intensive, with careful monitoring of the BCR-ABL1 molecular transcript and minimal residual disease. AlloSCT may be considered, especially for patients who do not achieve complete molecular remission or have high-risk genetic abnormalities, such as IKZF1-plus. If there is a loss of molecular response, it is essential to screen patients for ABL mutations and, ideally, change the TKI therapy. The T315I mutation is the most common mechanism for disease resistance, being targetable to ponatinib. Blinatumomab, a bispecific antibody, has shown significant synergy with TKIs in treating this disease. It serves as an excellent salvage therapy, aside from achieving outstanding results when incorporated into the frontline.
PubMed: 38136329
DOI: 10.3390/cancers15245783 -
Cell Dec 2023Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a...
Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.
Topics: Humans; Fragile X Syndrome; Trinucleotide Repeat Expansion; DNA Methylation; Mutation; Fragile X Mental Retardation Protein
PubMed: 38134876
DOI: 10.1016/j.cell.2023.11.019 -
Current Issues in Molecular Biology Dec 2023Inherited retinal diseases (IRDs) are a significant contributor to visual loss in children and young adults, falling second only to diabetic retinopathy. Understanding...
Inherited retinal diseases (IRDs) are a significant contributor to visual loss in children and young adults, falling second only to diabetic retinopathy. Understanding the pathogenic mechanisms of IRDs remains paramount. Some autosomal genes exhibit random allelic expression (RAE), similar to X-chromosome inactivation. This study identifies RAE genes in IRDs. Genes in the Retinal Information Network were cross-referenced with the recent literature to identify expression profiles, RAE, or biallelic expression (BAE). Loss-of-function intolerance (LOFI) was determined by cross-referencing the existing literature. Molecular and biological pathways that are significantly enriched were evaluated using gene ontology. A total of 184 IRD-causing genes were evaluated. Of these, 31 (16.8%) genes exhibited RAE. LOFI was exhibited in 6/31 (19.4%) of the RAE genes and 18/153 (11.8%) of the BAE genes. Brain tissue exhibited BAE in 107/128 (83.6%) genes for both sexes. The molecular pathways significantly enriched among BAE genes were photoreceptor activity, tubulin binding, and nucleotide/ribonucleotide binding. The biologic pathways significantly enriched for RAE genes were equilibrioception, parallel actin filament bundle assembly, photoreceptor cell outer segment organization, and protein depalmitoylation. Allele-specific expression may be a mechanism underlying IRD phenotypic variability, with clonal populations of embryologic precursor cells exhibiting RAE. Brain tissue preferentially exhibited BAE, possibly due to selective pressures against RAE. Pathways critical for cellular and visual function were enriched in BAE, which may offer a survival benefit.
PubMed: 38132471
DOI: 10.3390/cimb45120625 -
Hematology Reports Nov 2023In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and... (Review)
Review
In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and chemo-free regimens. Our objective was to analyze all recent trials evaluating these treatments and to compare them in terms of efficacy. We applied the Shiny method, an artificial intelligence technique, to analyze Kaplan-Meier curves and reconstruct patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and subjected to indirect head-to-head treatment comparisons. The endpoint was progression-free survival (PFS). Based on 432 reconstructed patients, eight trials were analyzed. The survival data from these trials were pooled into three types of treatments: (i) treatments based on tyrosine kinase inhibitors (TKIs) combined with reduced-intensity chemotherapy (denoted as TKICHE); (ii) TKIs associated with steroids with no chemotherapy (TKISTE); (iii) chemotherapy-free combinations of blinatumomab plus TKIs (TKIBLI). According to the Shiny method, the three PFS curves were reported in a single Kaplan-Meier graph and subjected to survival statistics. In terms of PFS, TKIBLI ranked first, TKICHE second, and TKISTE third; the differences between these three regimens were statistically significant. This multi-treatment Kaplan-Meier graph, generated through the Shiny method, summarized the current evidence on these treatments in both qualitative and quantitative terms.
PubMed: 38132276
DOI: 10.3390/hematolrep15040068