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Indian Journal of Pathology &... Mar 2024Recurrent somatic mutations in the JAK2, CALR, and the MPL genes are noted in BCR: ABL1 negative classic myeloproliferative neoplasms (MPN) that includes polycythemia...
Prevalence and clinicopathological features of driver gene mutations profile in BCR: ABL1 negative classical myeloproliferative neoplasm-A single-center study from North India.
BACKGROUND
Recurrent somatic mutations in the JAK2, CALR, and the MPL genes are noted in BCR: ABL1 negative classic myeloproliferative neoplasms (MPN) that includes polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF).
MATERIALS AND METHODS
Mutation profile and clinical features of MPN cases diagnosed at a tertiary care center in North India are being described. JAK2V617F mutation was screened using ARMS PCR, and CALR mutation was screened using allele-specific PCR followed by fragment analysis. MPL and JAK2 Exon 12 mutations were screened by Sanger sequencing. Some of the samples were also screened using commercial kits based on single-plex RT PCR.
RESULTS
A total of 378 cases (including 124 PV, 121 ET, and 133 PMF cases) were screened over 6.5 years. JAK2V617F mutation was noted in 90.3%, 61.1%, and 69.2% of cases of PV, ET, and PMF, respectively. In PV, JAK2V617F wild-type cases were associated with a significantly lower age (44 yrs vs 54 yrs; P = 0.001), lower TLC (6.3 vs 16.9; P = 0.001), and a lower platelet count (188 × 109/L vs 435 × 109/L; P = 0.009) as compared to the JAK2V617F mutated cases. CALR and MPL mutations were noted in 17.4% and 12% and 0.8% and 5.3% of ET and PMF cases, respectively. Type 1 CALR mutations were commoner in both ET and PMF. The triple negative cases constituted 20.7% and 13.5% cases of ET and PMF, respectively. In ET, the triple negative cases were found to have a significantly lower median age of presentation (42 yrs vs 52 yrs; P = 0.001), lower median TLC (10.2 × 109/L vs 13.2 × 109/L; P = 0.024), and a higher median platelet count (1238 × 109/L vs 906 × 109/L; P = 0.001) as compared to driver genes mutated cases. In PMF, the triple negative cases were found to have a significantly lower hemoglobin level (7.9 g/dl vs 11.0 gl/dl; P = 0.001) and a significant female preponderance (P = 0.05) as compared to the mutated cases. CALR mutations were found to have a significantly lower median age (43 yrs vs 56 yrs; P = 0.001) and lower hemoglobin (9.6 g/dl vs 11.3 g/dl) as compared to the JAK2 mutations.
CONCLUSION
Our data on the driver gene mutational profile of BCR: ABL1 negative MPN is one of the largest patient cohorts. The prevalence and clinicopathological features corroborate with that of other Asian studies.
PubMed: 38718214
DOI: 10.4103/ijpm.ijpm_743_23 -
Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.Blood Cancer Discovery Jul 2024Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to...
Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.
Topics: Chromosomes, Human, Pair 8; Humans; Trisomy; Proto-Oncogene Proteins c-myc; Calgranulin B; Myeloproliferative Disorders; Animals; Mice; Primary Myelofibrosis; Signal Transduction
PubMed: 38713018
DOI: 10.1158/2643-3230.BCD-23-0210 -
Myelofibrosis associated with immune cytopenia in an infant: a diagnostic and therapeutic challenge.Pediatric Hematology and Oncology May 2024
PubMed: 38712347
DOI: 10.1080/08880018.2024.2350424 -
Frontiers in Medicine 2024JAK/STAT pathway signalling is associated with both chronic inflammatory conditions such as psoriasis and haematological malignancies such as the myeloproliferative...
JAK/STAT pathway signalling is associated with both chronic inflammatory conditions such as psoriasis and haematological malignancies such as the myeloproliferative neoplasms (MPNs). Here we describe a 73yo female patient with a history of chronic plaque psoriasis, post-essential thrombocythemia myelofibrosis (MF) and a quality of life substantially impacted by both conditions. We report that 15 mg oral Methotrexate (MTX) weekly as a monotherapy is well tolerated, provides a substantial clinical improvement for both conditions and significantly improves quality of life. We suggest that the recently identified mechanism of action of MTX as a JAK inhibitor is likely to explain this efficacy and suggest that repurposing MTX for MPNs may represent a clinical- and cost-effective therapeutic option.
PubMed: 38698784
DOI: 10.3389/fmed.2024.1285772 -
British Journal of Haematology May 2024We describe the clinical phenotype, management strategies and outcomes of 22 patients with autoimmune myelofibrosis (AIMF); median age: 45 years; 77% females; 83% with...
We describe the clinical phenotype, management strategies and outcomes of 22 patients with autoimmune myelofibrosis (AIMF); median age: 45 years; 77% females; 83% with autoimmune disease, pancytopenia in 32% and transfusion-requiring anaemia in 59%. All informative cases were negative for JAK2 (n = 18) and CALR/MPL mutations (n = 12). Fourteen of nineteen (74%) evaluable patients achieved complete response (CR) based on the resolution of cytopenias. First-line treatments included steroids +/- immunosuppressive agents, cyclosporin and mycophenolate with CR in 7 of 13 (54%), 1 of 2 (50%) and 1 of 2 (50%) respectively. Rituximab salvage therapy yielded CR in 4 of 5 (80%) cases. The current study provides information on steroid-sparing treatments for AIMF.
PubMed: 38698680
DOI: 10.1111/bjh.19499 -
Blood May 2024
Gagelmann N, Badbaran A, Salit RB, et al. Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation. Blood. 2023;141(23):2901-2911.
Topics: Humans; Hematopoietic Stem Cell Transplantation; Primary Myelofibrosis; Tumor Suppressor Protein p53; Prognosis; Treatment Outcome; Female; Male
PubMed: 38696200
DOI: 10.1182/blood.2024024466 -
Avicenna Journal of Medicine Jan 2024The megakaryocyte and platelet inhibitory receptor gene G6P (MPIG6B) is located on chromosome 6p21.33. It encodes G6b-B; an inhibitory receptor expressed on the surface...
The megakaryocyte and platelet inhibitory receptor gene G6P (MPIG6B) is located on chromosome 6p21.33. It encodes G6b-B; an inhibitory receptor expressed on the surface of platelets. It regulates platelets production, aggregation, and activation. We describe a case of a 31-year-old man who presented with a long history of thrombocytopenia, anemia, and hepatosplenomegaly. The patient received multiple blood transfusions and his clinical course was stable. A bone marrow biopsy showed morphologic features similar to primary myelofibrosis. Whole exome sequencing study was performed and revealed homozygous pathogenic mutation in exon 2 of MPIG6B gene (c.324C > A, p.Cys108Ter) that is the second reported case in literature. In this report, we describe the main clinical and pathologic features of this disease and review the literature of previously documented cases.
PubMed: 38694137
DOI: 10.1055/s-0044-1779697 -
Leukemia & Lymphoma Apr 2024Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability...
Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls ( = 519, = 13,431, and = 18,183, respectively). Total healthcare costs were significantly higher for cases versus controls in each cohort (mean cost difference: MF, $67,456; PV, $10,970; ET, $22,279). Cases were more likely than controls to take disability leave and incurred higher disability-related costs. Among subgroups with thrombotic events, direct and indirect costs were higher for cases versus controls. Thrombotic events substantially increased direct costs and disability leave for patients with PV or ET compared with the full PV or ET cohorts. These findings demonstrate increased economic burden for patients with MPNs.
PubMed: 38676959
DOI: 10.1080/10428194.2024.2338849 -
Journal of Clinical Medicine Apr 2024: Philadelphia-negative chronic myeloproliferative neoplasms are a group of clonal hematopoietic disorders including polycythemia vera, essential thrombocythemia, and...
: Philadelphia-negative chronic myeloproliferative neoplasms are a group of clonal hematopoietic disorders including polycythemia vera, essential thrombocythemia, and primary myelofi-brosis. These neoplasms are characterized by an increased risk of thrombotic complications. Several studies have highlighted that the study of vessels of the retina offers the opportunity to visualize, in vivo, the damage to microcirculation that is common in various systemic pathologies. in our study, forty patients underwent an ophthalmological examination, using non-invasive imaging tech-niques, for analyses of their retinal vascularization. The objective was to correlate the findings ob-tained from this study of the retina with different markers of thrombotic risk, to demonstrate the usefulness of studying retinal vessels as a possible new prognostic biomarker of thrombotic risk in patients affected by Philadelphia-negative chronic myeloproliferative neoplasms. retinal imaging demonstrated changes in the microcirculation, with a reduced vascular density of the deep and superficial capillary plexuses with respect to a normal group, and a correlation between retinal changes and blood parameters. additional research will allow us to determine whether retinal changes in individuals with chronic myeloproliferative neoplasms could be predictive of the development of thrombotic events in these subjects.
PubMed: 38673505
DOI: 10.3390/jcm13082232 -
Life (Basel, Switzerland) Apr 2024To investigate the prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), platelet count and their ratios, neutrophil-lymphocyte ratio (NLR) and...
AIM
To investigate the prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), platelet count and their ratios, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), to thrombotic risk in patients with prefibrotic and overt fibrotic myelofibrosis (MF).
METHODS
We retrospectively analyzed a cohort of 256 patients with prefibrotic (85 patients) and overt fibrotic MF (171 patients) treated in six Croatian hematological centers.
RESULTS
Prefibrotic compared to overt fibrotic MF patients presented with significantly higher ALC, platelet count and PLR, and experienced longer time to thrombosis (TTT). Among prefibrotic patients, ANC > 8.33 × 10/L (HR 13.08, = 0.036), ALC > 2.58 × 10/L (HR 20.63, = 0.049) and platelet count > 752 × 10/L (HR 10.5, = 0.043) remained independently associated with shorter TTT. Among overt fibrotic patients, ANC > 8.8 × 10/L (HR 4.49, = 0.004), ALC ≤ 1.43 × 10/L (HR 4.15, = 0.003), platelet count ≤ 385 × 10/L (HR 4.68, = 0.004) and chronic kidney disease (HR 9.07, < 0.001) remained independently associated with shorter TTT.
CONCLUSIONS
Prognostic properties of ANC, ALC and platelet count are mutually independent and exceed those of NLR and PLR regarding thrombotic risk stratification. ALC and platelet count associate in opposite directions with thrombotic risk in prefibrotic and overt fibrotic MF patients.
PubMed: 38672793
DOI: 10.3390/life14040523