myeloproliferative neoplasm
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2022 ◽  
Vol 4 (3) ◽  
pp. e36-e43
Author(s):  
Rebecca Smith ◽  
Bashir Mohamed ◽  
Jeremy Nettleton

BackgroundMyeloid sarcoma is a rare extramedullary tumour of immature granulocytes, most commonly involving the skin, bone, lymph nodes, and soft tissue. It is usually associated with a diagnosis of relapsed or de novo acute myeloid leukaemia, acute lymphoblastic transformation of a myelodysplastic/myeloproliferative neoplasm, or can occur as isolated myeloid sarcoma.Case reportA 66-year-old female with a 7-year history of stable chronic myelomonocytic leukaemia presents with urgency, frequency, dysuria symptoms, and without new constitutional symptoms. She is found to have atypical, multifocal lesions on the right posterolateral wall of the bladder with associated hydronephrosis. Pathology reveals the diagnosis as myeloid sarcoma; surprisingly, bone marrow evaluation does not show evidence of acute leukaemic transformation.ConclusionsMyeloid sarcoma occurring in patients with chronic myelomonocytic leukaemia is extremely rare, and there are no cases reported in the English literature of these patients developing lesions in the bladder. The urological manifestations of an underlying haematological malignancy are best managed with a combination of systemic chemotherapy and allogeneic stem cell transplant, and in this case, the only surgical intervention required was ureteric stenting and tissue biopsy. Although rare, it is essential to consider alternative diagnoses when confronted with an atypical bladder tumour; failure to do so may result in patient harm by exposure to unnecessary intervention and delay to potentially curative treatment.


Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 113
Author(s):  
Elena Genovese ◽  
Margherita Mirabile ◽  
Sebastiano Rontauroli ◽  
Stefano Sartini ◽  
Sebastian Fantini ◽  
...  

Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidant capacity (TAC) correlate with detrimental clinical features, such as high levels of lactate dehydrogenase (LDH) and circulating CD34+ cells. Moreover, in JAK2-mutated patients, high plasma level of TAC is also associated with a poor overall survival (OS), and multivariate analysis demonstrated that high TAC classification is an independent prognostic factor allowing the identification of patients with inferior OS in both DIPSS lowest and highest categories. Altogether, our data suggest that a different capability to respond to oxidative stress can be one of the mechanisms underlying disease progression of myelofibrosis.


F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 1288
Author(s):  
Mohammad Al Hamad

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm generated by reciprocal chromosomal translocation, t (9; 22) (q34; q11) in the transformed hematopoietic stem cell. Tyrosine kinase inhibitors (TKIs) target the mature proliferating BCR-ABL cells, the major CML driver, and increase overall and disease-free survival. However, mutant clones, pre-existing or due to therapy, develop resistance against TKIs. BCR-ABL1 oncoprotein activates various molecular pathways including the RAS/RAF/MEK/ERK pathway, JAK2/STAT pathway, and PI3K/AKT/mTOR pathway. Stimulation of these pathways in TKI resistant CML patients, make them a new target. Moreover, a small proportion of CML cells, leukemic stem cells (LSCs), persist during the TKI therapy and sustain the disease in the patient. Engraftment of LSCs in the bone marrow niche and dysregulation of miRNA participate greatly in the TKI resistance. Current efforts are needed for determining the reason behind TKI resistance, identification, and elimination of CML LSC might be of great need for cancer cure.


Hemato ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 769-780
Author(s):  
Uzma Faruqi ◽  
Karen A. Breen

Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are clonal haematopoietic stem cell disorders. Of the MPNs, polycythaemia vera (PV) and essential thrombocythaemia (ET) confer a high thrombotic risk which may be the presenting feature of the disease. Thrombotic complications consist of both arterial and venous events and the presence of the JAK2 V617F mutation is associated with higher risk. Patients presenting with an unprovoked thrombus, particularly at an unusual site, e.g., splanchnic circulation, should be screened for the presence of this mutation. Historically, warfarin has been the only option for oral anticoagulation; however, there is now increasing evidence and practise to use direct oral anticoagulants (DOACs) in cancer. The seminal randomised control trials have demonstrated non-inferiority compared to low molecular weight heparin (LMWH) with a preferable bleeding profile. DOACs are now the first line treatment for atrial fibrillation and venous thromboembolic disease, as recommended by NICE, and therefore there is increasing familiarity with these agents. Furthermore, there are now targeted antidotes available. This paper reviews evidence for efficacy and safety of DOACs in MPN. Whilst no randomised control trials have been performed, several retrospective studies and reviews of registry data have reproducibly demonstrated that, alongside cytoreduction, DOACs represent an effective modality of anticoagulation for treatment of venous thromboembolism in MPN. Furthermore, dosing regimens provide the option for longer term secondary prophylaxis. Use of DOACs in arterial thrombosis is an area for future development and there is already some evidence for utility in peripheral vascular disease.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Taruni Pandhiri ◽  
Santhosh Kumar Pasupuleti ◽  
Baskar Ramdas ◽  
Rahul Kanumuri ◽  
Reuben Kapur

Obesity is an increasing epidemic disease world-wide responsible for enhancing the risk for developing Type 2 diabetes mellitus (T2DM) as well as cancer. However, it is unclear if and how obesity contributes to the transformation of pre-leukemic stem and progenitors (pre-LHSC/Ps) into full-blown leukemia such as acute myeloid leukemia (AML) or severe form of myeloproliferative neoplasm (MPN). We hypothesized that obesity induced chronic inflammation might be responsible for clonal selection of pre-LHSC/Ps bearing pre-leukemic mutations such as DNA methyltransferase 3A (DNMT3A) and for promoting the progression of early-onset MPN towards severe forms of AML/leukemia. To test this hypothesis, we genetically crossed pre-leukemic Dnmt3a+/-;Mx-Cre+ mice with leptin deficient obese (LepOb/Ob) mice to obtain Ob/Ob;Dnmt3a+/-;Mx-Cre+ compound mutant mice. Further, the Dnmt3a gene was deleted by giving the PolyIC and the deletion was confirmed through PCR. After 12 days of post-PolyIC the myeloid cells (neutrophils and monocytes) were expanded in Ob/Ob;Dnmt3a+/-;Mx-Cre+ mice compared to Dnmt3a+/-;Mx-Cre+, Dnmt3a+/-;Mx-Cre-, Ob/Ob and WT mice. We have harvested and analyzed all these mice after 26 days of post-PolyIC. Interestingly, Ob/Ob;Dnmt3a+/-;Mx-Cre+ mice showed increased BM cellularity, both the frequency of lineage negative, Sca-1+ and c-KIT+ (LSK) cells, short-term hematopoietic stem cells (ST-HSCs; LSK/CD48+/CD150-), granulocyte macrophage progenitor (GMPs; LSK/CD16+/CD34+), and reduction in LT-HSCs (LT-HSCs; LSK/CD48-/CD150+) compared to other groups. Flow cytometry analysis of PB, BM and spleen from Ob/Ob;Dnmt3a+/-;Mx-Cre+ mice demonstrated a significant increase in the frequency of mature myeloid cells (Gr-1+/Mac-1+) and a profound reduction in B220+ B cells compared to other groups. Remarkably, these mice also showed splenomegaly, elevated heart size and early signs of AML blasts as reflected by the presence of c-KIT+/CD11b+ double positive cells in the BM, consistent with severe MPN/AML development. Taken together, these results demonstrate that obesity induced inflammation cooperates with pre-leukemic Dnmt3a+/- mutation to induce an early-onset of severe MPN/AML like disease.       


Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 113-121
Author(s):  
Michael J. Mauro

Abstract Beginning with imatinib and now spanning 6 oral, highly active, and mostly safe agents, the development of specific targeted therapy for patients with chronic myeloid leukemia (CML) has created a new world featuring chronic maintenance chemotherapy for all treated as such, treatment-free remission, and functional cure after prolonged deep remission in a subset. As a result comes a necessary shift in focus from acute to chronic toxicity, increasing attention to patient comorbidities, and critical thinking around specific adverse events such as metabolic, cardiovascular, and cardiopulmonary effects, which vary from agent to agent. This review aims to pull together the state of the art of managing the “C” in CML—a chronic myeloproliferative neoplasm treated at present over many years with oral BCR-ABL-targeted agents in a population whose overall health can be complex and potentially affected by disease and therapy—and determine how we can better manage a highly treatable and increasingly curable cancer.


PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0251995
Author(s):  
Carla Casu ◽  
Alison Liu ◽  
Gianluca De Rosa ◽  
Audrey Low ◽  
Aae Suzuki ◽  
...  

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm resulting from an acquired driver mutation in the JAK2 gene of hematopoietic stem and progenitor cells resulting in the overproduction of mature erythrocytes and abnormally high hematocrit, in turn leading to thromboembolic complications. Therapeutic phlebotomy is the most common treatment to reduce the hematocrit levels and consequently decrease thromboembolic risk. Here we demonstrate that, by using the iron restrictive properties of the antisense oligonucleotides against Tmprss6 mRNA, we can increase hepcidin to achieve effects equivalent to therapeutic phlebotomy. We provide evidence that this less invasive approach could represent an additional therapeutic tool for the treatment of PV patients.


2021 ◽  
Vol 11 ◽  
Author(s):  
Sarah A. Wall ◽  
Ying Huang ◽  
Ashleigh Keiter ◽  
Allesia Funderburg ◽  
Colin Kloock ◽  
...  

The incidence of hematologic malignancies (HMs) is highest in the seventh decade of life and coincides with increasing occult, age-related vulnerabilities. Identification of frailty is useful in prognostication and treatment decision-making for older adults with HMs. This real-world analysis describes 311 older adults with HMs evaluated in a multidisciplinary oncogeriatric clinic. The accumulation of geriatric conditions [1-unit increase, hazards ratio (HR) = 1.13, 95% CI 1.00–1.27, p = 0.04] and frailty assessed by the Rockwood Clinical Frailty Scale (CFS, mild/moderate/severe frailty vs. very fit/well, HR = 2.59, 95% CI 1.41–4.78, p = 0.002) were predictive of worse overall survival. In multivariate analysis, HM type [acute leukemia, HR = 3.84, 95% CI 1.60–9.22, p = 0.003; myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN)/bone marrow failure, HR = 2.65, 95% CI 1.10–6.35, p = 0.03], age (per 5-year increase, HR = 1.46, 95% CI 1.21–1.76, p < 0.001), hemoglobin (per 1 g/dl decrease, HR = 1.21, 95% CI 1.05–1.40, p = 0.009), deficit in activities of daily living (HR = 2.20, 95% CI 1.11–4.34, p = 0.02), and Mini Nutrition Assessment score (at-risk of malnutrition vs. normal, HR = 2.00, 95% CI 1.07–3.73, p = 0.03) were independently associated with risk of death. The most commonly prescribed geriatric interventions were in the domains of audiology (56%) and pharmacy (54%). The Rockwood CFS correlated with prescribed interventions in nutrition (p = 0.01) and physical function (p < 0.001) domains. Geriatric assessment with geriatric intervention can be practically integrated into the routine care of older adults with HMs.


2021 ◽  
Vol 10 ◽  
pp. e2127
Author(s):  
Elham Abedi ◽  
Mehran Karimi ◽  
Nader Cohan ◽  
Sezaneh Haghpanah ◽  
Ramin Yaghobi ◽  
...  

Background: Myeloproliferative neoplasms (MPNs) are heterogeneous disorders with a variety of genetic abnormalities. We aim to assess the prevalence of Calreticulin (CALR) and JAK2 mutations in Iranian MPNs. Materials and Methods: In a cross-sectional study, CALR and JAK2 mutations among 130 MPNs patients, including 78 Philadelphia chromosome-negative (MPN-) and 52 Philadelphia chromosome-positive (MPN+) as well as 51 healthy control subjects, were investigated by GAP-PCR. Results: In MPN- group JAK2 and CALR gene mutations were found in 64.1% and 7.7%, respectively, that 5.1% were positive for both mutations, and 2.6% had only CALR mutation. In polycythemia vera (PV) patients 90% had JAK2 mutation, which was significantly higher than other MPN- or MPN+ patients. Most of the MPN+ patients had neither mutation in CALR nor JAK2 (70% CALR-/JAK2-). Among all patients’ groups, the prevalence of CALR+ mutation in either rs1450785140 (4 cases) or rs765476509 (5 cases) position was not statistically different. Conclusion: These results showed a low prevalence of CALR mutations in all types of MPNs in the Iranian population that its frequency may influence by ethnicity and genetic diversity. CALR mutation may be seen in JAK2 negative cases, also. The PV had the highest JAK2 mutation with a 90 percent positivity rate among MPNs cases. [GMJ.2021;10:e2127]


MD-Onco ◽  
2021 ◽  
Vol 1 (1) ◽  
pp. 61-65
Author(s):  
Yu. E. Ryabukhina ◽  
P. A. Zeynalova ◽  
O. I. Timofeeva ◽  
F. M. Abbasbeyli ◽  
T. V. Ponomarev ◽  
...  

Chronic myeloproliferative neoplasms (CMPN), Ph-negative, are of clonal nature, develop on the level of hematopoietic stem cell and are characterized by proliferation of one or more hematopoietic pathways. Currently, the group of Ph-negative CMPN includes essential thrombocythemia, primary myelofibrosis, polycythemia vera, myeloproliferative neoplasm unclassifiable.Identification of mutations in the Jak2 (V617F), CALR, and MPL genes extended understanding of biological features of Ph-negative CMPN and improved differential diagnosis of myeloid neoplasms. Nonetheless, clinical practice still encounters difficulties in clear separation between such disorders as primary myelofibrosis, early-stage and transformation of essential thrombocythemia into myelofibrosis with high thrombocytosis. Thrombocytosis is one of the main risk factors for thromboembolic complications, especially in elderly people.A clinical case of an elderly patient with fracture of the left femur developed in the context of Ph-negative CMPN (myelofibrosis) with high level of thrombocytosis is presented which in combination with enforced long-term immobilization and presence of additional risk created danger of thrombosis and hemorrhage during surgery and in the postoperative period.


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