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ELife Jun 2024Philadelphia chromosome-positive (Ph) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved...
Philadelphia chromosome-positive (Ph) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph leukemia.
Topics: Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Animals; Mice; NEDD8 Protein; Cell Line, Tumor; Ubiquitin-Protein Ligases
PubMed: 38865175
DOI: 10.7554/eLife.88375 -
Cell Reports Jun 2024Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells...
Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.
PubMed: 38861385
DOI: 10.1016/j.celrep.2024.114323 -
Frontiers in Immunology 2024The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an...
INTRODUCTION
The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypotheses of how the treatment works.
MATERIALS AND METHODS
We present an extension of the Cancitis model, which describes the development of myeloproliferative neoplasms and their interactions with inflammation, that explicitly models progenitor cells and can account for treatment with ruxolitinib through effects on the malignant stem cell response to cytokine signalling and the death rate of malignant progenitor cells. The model has been fitted to individual patients' data for the V617F variant allele frequency from the COMFORT-II and RESPONSE studies for patients who had substantial reductions (20 percentage points or 90% of the baseline value) in their V617F variant allele frequency ( = 24 in total).
RESULTS
The model fits very well to the patient data with an average root mean square error of 0.0249 (2.49%) when allowing ruxolitinib treatment to affect both malignant stem and progenitor cells. This average root mean square error is much lower than if allowing ruxolitinib treatment to affect only malignant stem or only malignant progenitor cells (average root mean square errors of 0.138 (13.8%) and 0.0874 (8.74%), respectively).
DISCUSSION
Systematic simulation studies and fitting of the model to the patient data suggest that an initial reduction of the malignant cell burden followed by a monotonic increase can be recapitulated by the model assuming that ruxolitinib affects only the death rate of malignant progenitor cells. For patients exhibiting a long-term reduction of the malignant cells, the model predicts that ruxolitinib also affects stem cell parameters, such as the malignant stem cells' response to cytokine signalling.
Topics: Nitriles; Humans; Pyrazoles; Pyrimidines; Myeloproliferative Disorders; Janus Kinase 2; Neoplastic Stem Cells; Models, Theoretical; Protein Kinase Inhibitors
PubMed: 38846951
DOI: 10.3389/fimmu.2024.1384509 -
Biology of Sex Differences Jun 2024Sex hormones and sex chromosomes play a vital role in cardiovascular disease. Testosterone plays a crucial role in men's health. Lower testosterone level is associated...
BACKGROUND
Sex hormones and sex chromosomes play a vital role in cardiovascular disease. Testosterone plays a crucial role in men's health. Lower testosterone level is associated with cardiovascular and cardiometabolic diseases, including inflammation, atherosclerosis, and type 2 diabetes. Testosterone replacement is beneficial or neutral to men's cardiovascular health. Testosterone deficiency is associated with cardiovascular events. Testosterone supplementation to hypogonadal men improves libido, increases muscle strength, and enhances mood. We hypothesized that sex chromosomes (XX and XY) interaction with testosterone plays a role in arterial stiffening.
METHODS
We used four core genotype male mice to understand the inherent contribution of sex hormones and sex chromosome complement in arterial stiffening. Age-matched mice were either gonadal intact or castrated at eight weeks plus an additional eight weeks to clear endogenous sex hormones. This was followed by assessing blood pressure, pulse wave velocity, echocardiography, and ex vivo passive vascular mechanics.
RESULTS
Arterial stiffening but not blood pressure was more significant in castrated than testes-intact mice independent of sex chromosome complement. Castrated mice showed a leftward shift in stress-strain curves and carotid wall thinning. Sex chromosome complement (XX) in the absence of testosterone increased collagen deposition in the aorta and Kdm6a gene expression.
CONCLUSION
Testosterone deprivation increases arterial stiffening and vascular wall remodeling. Castration increases Col1α1 in male mice with XX sex chromosome complement. Our study shows decreased aortic contractile genes in castrated mice with XX than XY sex chromosomes.
Topics: Animals; Male; Testosterone; Vascular Stiffness; Sex Chromosomes; Mice; Mice, Inbred C57BL; Blood Pressure; Orchiectomy
PubMed: 38845040
DOI: 10.1186/s13293-024-00624-0 -
Haematologica Jun 2024Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the...
Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.
Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs.
PubMed: 38841802
DOI: 10.3324/haematol.2023.284853 -
Haematologica Jun 2024The treatment of childhood acute lymphoblastic leukemia (ALL) has reached overall survival rates exceeding 90%. The present and future challenges are to cure the... (Review)
Review
The treatment of childhood acute lymphoblastic leukemia (ALL) has reached overall survival rates exceeding 90%. The present and future challenges are to cure the remainder of patients still dying from disease, and to reduce morbidity and mortality in those who can be cured with standard-of-care chemotherapy by replacing toxic chemotherapy elements while retaining cure rates. With the novel therapeutic options introduced in the last years, including immunotherapies and targeted antibodies, the treatment of ALL is undergoing major changes. For B-cell precursor ALL, blinatumomab, an anti-CD19 bispecific antibody, has established its role in the consolidation treatment for both high- and standard-risk first relapse of ALL, in the presence of bone marrow involvement, and may also have an impact on the outcome of high-risk subsets such as infant ALL and Philadelphia chromosome-positive ALL. Inotuzumab ozogamicin, an anti-CD22 drug conjugated antibody, has demonstrated high efficacy in inducing complete remission in relapsed ALL, even in the presence of high tumor burden, but randomized phase III trials are still ongoing. For T-ALL the role of CD38-directed treatment, such as daratumumab, is gaining interest, but randomized data are needed to assess its specific benefit. These antibodies are currently being tested in patients with newly diagnosed ALL and may lead to major changes in the present paradigm of treatment of pediatric ALL. Unlike the past, lessons may be learned from innovations in adult ALL, in which more drastic changes are piloted that may need to be translated to pediatrics.
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Child; Molecular Targeted Therapy; Immunoconjugates; Antibodies, Bispecific; Antineoplastic Agents, Immunological; Treatment Outcome; Inotuzumab Ozogamicin
PubMed: 38832425
DOI: 10.3324/haematol.2023.283815 -
BMC Ophthalmology May 2024We describe a case in which bilateral optic nerve infiltration and leukemic retinopathy were the initial signs of disease relapse in a patient with Philadelphia...
BACKGROUND
We describe a case in which bilateral optic nerve infiltration and leukemic retinopathy were the initial signs of disease relapse in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) with central nervous system (CNS) involvement.
CASE PRESENTATION
A 65-year-old Asian female with Ph-ALL in complete remission presented at our institution with symptoms of visual disturbance, central scotoma and pain with eye movement in both eyes for a 1-month duration. Ophthalmic examination revealed remarkable optic disc swelling with multiple flame-shaped peripapillary hemorrhages, retinal venous dilation and retinal hemorrhages in both eyes. She was subsequently referred to the treating oncologist and diagnosed with Ph-ALL relapse with multiple relapsed diseases involving the bone marrow and CNS. After intrathecal (IT) therapy, her visual acuity dramatically improved, and her leukemic infiltrates decreased.
CONCLUSIONS
To the best of our knowledge, this is the first case report of ALL relapse with CNS involvement presenting as bilateral optic nerve infiltration and leukemic retinopathy in an adult. Hence, we highlight the priority and sensitivity of ophthalmic examinations, as they are noninvasive methods for detecting leukemia relapse.
Topics: Humans; Female; Aged; Leukemic Infiltration; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Optic Nerve; Retinal Diseases; Magnetic Resonance Imaging; Neoplasm Recurrence, Local; Visual Acuity
PubMed: 38807037
DOI: 10.1186/s12886-024-03486-7 -
ELife May 2024Solid tumors generally exhibit chromosome copy number variation, which is typically caused by chromosomal instability (CIN) in mitosis. The resulting aneuploidy can...
Solid tumors generally exhibit chromosome copy number variation, which is typically caused by chromosomal instability (CIN) in mitosis. The resulting aneuploidy can drive evolution and associates with poor prognosis in various cancer types as well as poor response to T-cell checkpoint blockade in melanoma. Macrophages and the SIRPα-CD47 checkpoint are understudied in such contexts. Here, CIN is induced in poorly immunogenic B16F10 mouse melanoma cells using spindle assembly checkpoint MPS1 inhibitors that generate persistent micronuclei and diverse aneuploidy while skewing macrophages toward a tumoricidal 'M1-like' phenotype based on markers and short-term anti-tumor studies. Mice bearing CIN-afflicted tumors with wild-type CD47 levels succumb similar to controls, but long-term survival is maximized by SIRPα blockade on adoptively transferred myeloid cells plus anti-tumor monoclonal IgG. Such cells are the initiating effector cells, and survivors make de novo anti-cancer IgG that not only promote phagocytosis of CD47-null cells but also suppress tumor growth. CIN does not affect the IgG response, but pairing CIN with maximal macrophage anti-cancer activity increases durable cures that possess a vaccination-like response against recurrence.
Topics: Animals; Chromosomal Instability; Mice; Macrophages; Immunoglobulin G; CD47 Antigen; Mice, Inbred C57BL; Melanoma, Experimental; Cell Line, Tumor; Female
PubMed: 38805560
DOI: 10.7554/eLife.88054 -
Cureus Apr 2024Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (Ph), resulting from the t(9;22)(q34;q11.2)...
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (Ph), resulting from the t(9;22)(q34;q11.2) translocation. Imatinib, a tyrosine kinase inhibitor (TKI), has revolutionized the treatment of CML. However, despite the initial response, some patients may progress to an advanced stage, such as a blast crisis. We report a 40-year-old female who presented with CML chronic phase (CP) taking imatinib 400 mg/day and achieved a complete hematological response (CHR) after one month of treatment. She achieved a suboptimal response in the third month (BCR-ABL positive 10.29% IS). However, five months into therapy, she developed a sudden lymphoid blast crisis with chromosomal aberrations involving chromosomes 10 and 12. Molecular analysis detected concomitant L248V with partial exon 4 deletion and E225V mutations within the BCR-ABL1 fusion gene. The patient received intensive chemotherapy and dasatinib. We report the first case of concomitant mutation of L248V with partial exon 4 deletion and E255V on BCR-ABL1 gene mutation, which contributes to a sudden precursor B-cell lymphoid blast crisis.
PubMed: 38800235
DOI: 10.7759/cureus.58972 -
Genes Apr 2024Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of the Philadelphia chromosome, a product of the reciprocal...
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of the Philadelphia chromosome, a product of the reciprocal translocation t(9;22)(q34;q11), in the BCR and ABL genes. These rearrangements in both genes lead to the formation of various fusion mRNA products, with preferential expression of , , and other mRNA variants, combined with additional chromosomal abnormalities. Notably, the distribution and frequency of different mRNA variants vary in different populations. However, studies concerning this in Mexico are limited, and the results have been inconclusive. This study therefore aimed to determine the distribution of mRNA variants in different clinical phases of CML and their effect on hematological parameters and patient survival. This study included 33 patients, whose demographic, clinical, and molecular data on mRNA variants and hematological parameters were collected to identify potential associations. A total of 84.8% (n = 28) of patients had translocation and increased platelet and basophil counts. The most frequent mRNA variant was (64.3%), followed by (28.6%) and (3.6%). Concerning the clinical phases of CML, 75.8% (n = 25), 21.2% (n = 7), and 3% (n = 1) of patients were in the chronic, blast, and accelerated phases, respectively. Moreover, the mRNA variant was more commonly identified in patients in the chronic phase. No correlation was observed between mRNA variant expression and patient survival. However, was indicative of patients with longer survival as well as those treated with imatinib or nilotinib. Additionally, platelet count could be a marker of translocation.
Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Female; Male; Middle Aged; Fusion Proteins, bcr-abl; Adult; Aged; RNA, Messenger; Imatinib Mesylate; Translocation, Genetic; Young Adult
PubMed: 38790196
DOI: 10.3390/genes15050567