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Molecular Biology Reports Jun 2024Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia... (Review)
Review
Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.
Topics: Humans; Renin-Angiotensin System; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Angiotensin II; Leukemia, Myeloid, Acute; Signal Transduction; Angiotensin I; Neovascularization, Pathologic; Animals; Peptide Fragments
PubMed: 38904729
DOI: 10.1007/s11033-024-09659-3 -
Blood Jun 2024
Topics: Humans; Translocation, Genetic; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 14; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Heterozygote; Male; Female
PubMed: 38900478
DOI: 10.1182/blood.2024023923 -
Frontiers in Oncology 2024The incidence of multiple primary tumors(MPTs) is on the rise in recent years, but patients having four or more primary tumors is still rare. Lynch syndrome (LS)...
The incidence of multiple primary tumors(MPTs) is on the rise in recent years, but patients having four or more primary tumors is still rare. Lynch syndrome (LS) patients have a high risk of developing MPTs. NGS sequencing could identify the genetic alterations in different tumors to make a definite diagnosis of uncommon cases in clinical practice. Here, we report the case of a 66-year-old female patient who develops four MPTS between the ages of 41 and 66, that is sigmoid colon cancer, acute non-lymphocytic leukemia, urothelial carcinoma and ascending colon cancer. She has survived for more than 26 years since the first discovery of tumor. Targeted sequencing indicates that she has a pathogenic germline mutation in the exon 13 of , and her 2020 ureteral cancer sample and 2023 colon cancer sample have completely different mutation profiles. To the best of our knowledge, this is the first case of multiple primary tumors with an acute non-lymphocytic leukemia in LS patients.
PubMed: 38894864
DOI: 10.3389/fonc.2024.1382154 -
International Journal of Molecular... May 2024Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying gene...
Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have garnered attention for their potential therapeutic efficacy in treating -rearranged acute leukemias. However, resistance to menin inhibition poses challenges, and identifying which patients would benefit from revumenib treatment is crucial. Here, we investigated the in vitro response to revumenib in -rearranged ALL and AML. While ALL samples show rapid, dose-dependent induction of leukemic cell death, AML responses are much slower and promote myeloid differentiation. Furthermore, we reveal that acquired resistance to revumenib in -rearranged ALL cells can occur either through the acquisition of mutations or independently of mutations in . Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in -rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in -rearranged acute leukemia.
Topics: Humans; Histone-Lysine N-Methyltransferase; Myeloid-Lymphoid Leukemia Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins; Methyltransferases; Leukemia, Myeloid, Acute; Drug Synergism; Gene Rearrangement; Cell Line, Tumor; Drug Resistance, Neoplasm; Mutation
PubMed: 38892207
DOI: 10.3390/ijms25116020 -
International Journal of Molecular... May 2024Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) develops from very early cells with the potential for both T-cell and myeloid differentiation. The...
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) develops from very early cells with the potential for both T-cell and myeloid differentiation. The ambiguous nature of leukemic blasts in ETP-ALL may lead to immunophenotypic alterations at relapse. Here, we address immunophenotypic alterations and related classification issues, as well as genetic features of relapsed pediatric ETP-ALL. Between 2017 and 2022, 7518 patients were diagnosed with acute leukemia (AL). In addition to conventional immunophenotyping, karyotyping, and FISH studies, we performed next-generation sequencing of the T-cell receptor clonal repertoire and reverse transcription PCR and RNA sequencing for patients with ETP-ALL at both initial diagnosis and relapse. Among a total of 534 patients diagnosed with T-cell ALL (7.1%), 60 had ETP-ALL (11.2%). Ten patients with ETP-ALL experienced relapse or progression on therapy (16.7%), with a median time to event of 5 months (ranging from two weeks to 5 years). Most relapses were classified as AL of ambiguous lineage (n = 5) and acute myeloid leukemia (AML) (n = 4). Major genetic markers of leukemic cells remained unchanged at relapse. Of the patients with relapse, four had polyclonal leukemic populations and a relapse with AML or bilineal mixed-phenotype AL (MPAL). Three patients had clonal rearrangements and relapse with AML, undifferentiated AL, or retention of the ETP-ALL phenotype. ETP-ALL relapse requires careful clinical and laboratory diagnosis. Treatment decisions should rely mainly on initial examination data, taking into account both immunophenotypic and molecular/genetic characteristics.
Topics: Humans; Child; Immunophenotyping; Male; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Female; Child, Preschool; Adolescent; Infant; Recurrence; Receptors, Antigen, T-Cell
PubMed: 38891797
DOI: 10.3390/ijms25115610 -
Cytotherapy May 2024The one-year survival rate for patients experiencing a relapse of B-cell acute lymphocytic leukemia (B-ALL) following hematopoietic stem cell transplantation (HSCT) is...
The one-year survival rate for patients experiencing a relapse of B-cell acute lymphocytic leukemia (B-ALL) following hematopoietic stem cell transplantation (HSCT) is approximately 30%. Patients experiencing a relapse after allogeneic HSCT frequently encounter difficulties in obtaining autologous CAR-T products. We conducted a study involving 14 patients who received donor-derived CAR-T therapy for relapsed B-ALL following HSCT between August 2019 and May 2023 in our center. The results revealed a CR/CRi rate of 78.6% (11/14), a GVHD rate of 21.4% (3/14), and a 1-year overall survival (OS) rate of 56%. Decreased bone marrow donor cell chimerism in 9 patients recovered after CAR-T therapy. The main causes of death were disease progression and infection. Further analysis showed that GVHD (HR 7.224, 95% CI 1.42-36.82, P = 0.017) and platelet recovery at 30 days (HR 6.807, 95% CI 1.61-28.83, P = 0.009) are significantly associated with OS after CAR-T therapy. Based on the findings, we conclude that donor-derived CAR-T cells are effective in treating relapsed B-ALL patients following HSCT. Additionally, GVHD and poor platelet recovery impact OS, but further verification with a larger sample size is needed.
PubMed: 38888526
DOI: 10.1016/j.jcyt.2024.05.021 -
Cancer Medicine Jun 2024Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL)...
BACKGROUND
Asparaginase is essential for treating T-cell acute lymphoblastic leukemia (T-ALL). Despite the ongoing debate on whether T-ALL and T-cell lymphoblastic lymphoma (T-LBL) are the same disease entity or two distinct diseases, patients with T-LBL often receive the same or similar treatment protocols as those with T-ALL.
METHODS
The outcomes of patients with or without L-asparaginase discontinuation were retrospectively analyzed among four national protocols: Japan Association of Childhood Leukemia Study (JACLS) ALL-02 and ALL-97 for T-ALL and Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 and JACLS NHL-98 for T-LBL. The hazard ratio (HR) was calculated with the Cox regression model by considering L-asparaginase discontinuation as a time-dependent variable.
RESULTS
In total, 199 patients with T-ALL, and 133 patients with T-LBL were included. L-asparaginase discontinuation compromised event-free survival (EFS) of T-ALL patients (ALL-02: HR 3.32, 95% confidence interval [CI] 1.40-7.90; ALL-97: HR 3.39, 95%CI 1.19-9.67). Conversely, EFS compromise was not detected among T-LBL patients (ALB-NHL03: HR 1.39, 95%CI 0.41-4.68; NHL-98: HR 0.92, 95%CI 0.11-7.60).
CONCLUSION
The effects of L-asparaginase discontinuation differed between T-ALL and T-LBL. We assume that the differential impact results from (1) the inherent differential response to L-asparaginase between them and/or (2) a less stringent assessment of early treatment response in T-LBL than in T-ALL. Given the poor salvage rate of refractory or relapsed T-ALL and T-LBL, optimization of the frontline therapy is critical, and the current study provides a new suggestion for further treatment modifications. However, larger studies in contemporary intensified treatment protocols are required.
Topics: Humans; Asparaginase; Child; Male; Female; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Child, Preschool; Retrospective Studies; Adolescent; Infant; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Japan; Antineoplastic Agents
PubMed: 38888368
DOI: 10.1002/cam4.7246 -
Mediterranean Journal of Hematology and... 2024The treatment outcomes of patients with chronic lymphocytic leukemia (CLL) have considerably improved with the introduction of targeted therapies based on Bruton kinase... (Review)
Review
The treatment outcomes of patients with chronic lymphocytic leukemia (CLL) have considerably improved with the introduction of targeted therapies based on Bruton kinase inhibitors (BTKIs), venetoclax, and anti-CD20 monoclonal antibodies. However, despite these consistent improvements, patients who become resistant to these agents have poor outcomes and need new and more efficacious therapeutic strategies. Among these new treatments, a potentially curative approach consists of the use of chimeric antigen receptor T (CAR-T) cell therapy, which achieved remarkable success in various B-cell malignancies, including B-cell Non-Hodgkin Lymphomas (NHLs) and B-acute lymphoblastic Leukemia (ALL). However, although CAR-T cells were initially used for the treatment of CLL, their efficacy in CLL patients was lower than in other B-cell malignancies. This review analyses possible mechanisms of these failures, highlighting some recent developments that could offer the perspective of the incorporation of CAR-T cells in treatment protocols for relapsed/refractory CLL patients.
PubMed: 38882451
DOI: 10.4084/MJHID.2024.045 -
Gan To Kagaku Ryoho. Cancer &... May 2024
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Homologous; Adult; Hematopoietic Stem Cell Transplantation; Philadelphia Chromosome
PubMed: 38881062
DOI: No ID Found -
Gan To Kagaku Ryoho. Cancer &... May 2024
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Immunotherapy, Adoptive; Receptors, Chimeric Antigen
PubMed: 38881061
DOI: No ID Found