High Mitochondrial Membrane Potential Identifies Patients with Myeloproliferative Neoplasms with a More Aggressive Natural History

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1992-1992
Author(s):  
Jeffrey R Gardner ◽  
Omar Abdel-Wahab ◽  
Mark Frattini ◽  
Joseph G Jurcic ◽  
Kristina Knapp ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Polycythemia Vera ◽  
Mitochondrial Membrane Potential ◽  
Essential Thrombocythemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Mitochondrial Membrane ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Acute Myeloid

Abstract Abstract 1992 The myeloproliferative neoplasms (MPN) can have a variable natural history. Polycythemia vera and essential thrombocythemia, in particular, are conditions that can extend over decades, but some patients have clinical progression to myelofibrosis or acute myeloid leukemia. As first articulated by Warburg, cancers are metabolically distinguished from normal tissues by the use of glycolysis under aerobic conditions. To metabolically characterize the blood cells of patients with myeloproliferative neoplasms, we measured the mitochondrial membrane potential using the cyanine dye, JC-1. In examining cells derived from the blood and/or marrow of 159 patients with primary myelofibrosis, polycythemia vera and essential thrombocythemia, we found that the mitochondrial membrane potential (FL2/FL1=electrochemical potential/mitochondrial mass) was elevated compared to the blood cells of normal individuals. Thirty five percent of patients with polycythemia vera and essential thrombocythemia had normal MMP. In contrast, 97% of patients with primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis and acute myeloid leukemia following an MPN had evidence of cell populations with higher mitochondrial membrane potential. Cells with distinctly higher mitochondrial membrane potential could be indentified in platelets and polymorphonuclear leukocytes; however the MMP of lymphocytes was normal, indicating that the alteration in metabolic state likely occurred in a multipotential myeloid stem cell. Cell populations were confirmed by co-staining with anti-CD19, -CD45, -GlycophorinA and -β3-integrin antibodies. Sequential analysis of patient samples found that the acquisition of higher mitochondrial membrane potential was stable and persistent over 2 years or more of follow up and that elevated membrane potential predisposed patients to disease progression. The balance of patients (65%) with ET had evidence of increased MMP suggesting the possibility of disease in an early state of evolution to a more aggressive condition. The increased MMP did not correlate with the presence of mutation in JAK2. These results indicate that clinically advanced MPN can be characterized by changes in mitochondrial physiology that might be identified non-invasively by flow cytometric staining with JC-1. In addition, the early nature of these changes may help to identify therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

Multilineage Dysplasia Is Associated with Worse Clinical Outcome Independent of the Diagnosis of Acute Myeloid Leukemia or Myelodysplastic Syndrome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1440-1440 ◽  
Author(s):  
Hesham M. Amin ◽  
Sherry A. Pierce ◽  
Elihu H. Estey ◽  
Hagop M. Kantarjian ◽  
Susan M. O’Brien ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Myeloid Leukemia ◽  
Mitochondrial Membrane ◽  
Who Classification ◽  
Annexin V ◽  
Potential Analysis ◽  
Multilineage Dysplasia ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematopoietic neoplasms. The World Health Organization (WHO) classification includes the two new categories: AML with dysplasia in more than one lineage (multilineage dysplasia; MLD) and refractory cytopenia with MLD. However, the relevance of dysplasia in one lineage versus more than one lineage and the importance of separating MDS with MLD from AML with MLD are not known. We studied 1110 patients with AML and 171 patients with MDS classified according to the WHO criteria and treated at MD Anderson Cancer Center from 1995 to 2003. All MDS patients had advanced disease requiring treatment and included 19 patients with refractory anemia (RA), 7 with RA with ringed sideroblasts (RARS), and 145 with RA with excess blasts (RAEB). Survival analysis showed no statistical significance in overall survival between MDS patients and AML patients when classified according to the WHO classification (P=0.196). When AML and MDS patients were considered as one group, but divided based on the presence or absence of MLD, patients with MLD had significantly shorter survival (P=.004; Figure 1). More importantly, multivariate Cox proportional hazard model showed that the shorter survival in the combined AML and MDS patients with MLD was independent of cytogenetic abnormalities, antecedent hematologic disease, performance status, and the original diagnosis of AML or MDS. As expected, shorter survival was found in AML patients with MLD as compared with those with no dysplasia or dysplasia of one lineage (P=.003). The presence of dysplasia in one lineage was irrelevant for the clinical course. Apoptosis detection using annexin V staining or mitochondrial membrane potential analysis showed significantly higher apoptosis in AML patients with MLD as compared with those patients without MLD and the presence of increased apoptosis correlated with shorter survival (P=.04). The present study demonstrates that the criteria established by the WHO classification for the diagnosis of AML and MDS can be significantly enhanced if the presence or absence of MLD is considered irrespective of the percentage of blasts. Furthermore, apoptosis can be detected in AML and MDS patients using annexin V staining or mitochondrial membrane potential analysis and it can be utilized to indirectly reflect the level of dysplasia in these patients. With the progress in targeted therapy, the classification of leukemia and myelodysplasia based on biological abnormalities may provide more helpful clues for therapy and clinical management. Figure Figure

scholarly journals Myeloproliferative neoplasms

JBMTCT ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 129
Author(s):  
Neysimelia Costa Villela ◽  
Gustavo Zamperlini ◽  
Patrícia Shimoda Ikeuti ◽  
Roseane Vasconcelos Gouveia ◽  
Simone De Castro Resende Franco ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Age Group ◽  
Pediatric Age ◽  
Pediatric Age Group ◽  
Low Incidence

  In addition to the chronic myeloid leukemia (CML) BCR-ABL1+, classic myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia and primary myelofibrosis. These have a very low incidence in the pediatric age group and there is no consensus on treatment in children.

scholarly journals Critical requirement for Stat5 in a mouse model of polycythemia vera

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3539-3549 ◽  
Author(s):  
Dongqing Yan ◽  
Robert E. Hutchison ◽  
Golam Mohi
Keyword(s):  
Polycythemia Vera ◽  
Blood Cells ◽  
Myeloproliferative Neoplasms ◽  
White Blood Cells ◽  
Strong Support ◽  
Primary Myelofibrosis ◽  
Blood Parameters ◽  
Critical Function ◽  
Critical Requirement ◽  
Multiple Signaling

The JAK2V617F mutation has been identified in most cases of Ph-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Expression of JAK2V617F results in constitutive activation of multiple signaling molecules/pathways. However, the key signaling downstream of JAK2V617F required for transformation and induction of MPNs remains elusive. Using a mouse genetic strategy, we show here that Stat5 is absolutely required for the pathogenesis of PV induced by Jak2V617F. Whereas expression of Jak2V617F in mice resulted in all the features of human PV, including an increase in red blood cells, hemoglobin, hematocrit, white blood cells, platelets, and splenomegaly, deletion of Stat5 in the Jak2V617F knockin mice normalized all the blood parameters and the spleen size. Furthermore, deletion of Stat5 completely abrogated erythropoietin (Epo)–independent erythroid colony formation evoked by Jak2V617F, a hallmark feature of PV. Re-expression of Stat5 in Stat5-deficient Jak2V617F knockin mice completely rescued the defects in transformation of hematopoietic progenitors and the PV phenotype. Together, these results indicate a critical function for Stat5 in the pathogenesis of PV. These findings also provide strong support for the development of Stat5 inhibitors as targeted therapies for the treatment of PV and other JAK2V617F-positive MPNs.

scholarly journals Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: A single center study

2019 ◽  
Vol 11 (4) ◽  
Author(s):  
Vincenzo Accurso ◽  
Marco Santoro ◽  
Simona Raso ◽  
Angelo Davide Contrino ◽  
Paolo Casimiro ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Clinical Manifestations ◽  
Primary Myelofibrosis ◽  
Thrombotic Risk ◽  
Single Center Study ◽  
The Impact ◽  
The Relationship

Splenomegaly is one of the major clinical manifestations of primary myelofibrosis and is common also in other chronic Philadelphia-negative myeloproliferative neoplasms, causing symptoms and signs and affecting quality of life of patients diagnosed with these diseases. We aimed to study the impact that such alteration has on thrombotic risk and on the survival of patients with essential thrombocythemia and patients with Polycythemia Vera (PV). We studied the relationship between splenomegaly (and its grade), thrombosis and survival in 238 patients with et and 165 patients with PV followed at our center between January 1997 and May 2019.

scholarly journals MPL W515 L/K mutations in myeloproliferative neoplasms

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Sohaila Eldeweny ◽  
Hosny Ibrahim ◽  
Ghada Elsayed ◽  
Mohamed Samra
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Ethnic Groups ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Myelogenous Leukemia ◽  
Egyptian Population ◽  
Ph Chromosome ◽  
Pathological Variant

Abstract Background Myeloproliferative neoplasms (MPNs) describe a group of diseases involving the bone marrow (BM). Classical MPNs are classified into chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). This classification is based on the presence of Philadelphia (Ph) chromosome (BCR/ABL1). CML is BCR/ABL1-positive while PV, ET, and PMF are negative. JAK2 p. Val617Phe pathological variant is the most associated mutation in BCR/ABL1-negative MPNs. The frequency of JAK2 p. Val617Phe is 90–95% in PV patients, 50–60% in ET, and 40–50% in patients with PMF. Studies on MPL gene led to the revelation of a gain of function pathological variants in JAK2 p. Val617Phe-negative myeloproliferative neoplasms (MPNs). MPL p. W515 L/K pathological variants are the most common across all mutations in MPL gene. The prevalence of these pathological variants over the Egyptian population is not clear enough. In the present study, we aimed to investigate the prevalence of MPL p. W515 L/K pathological variants in the Philadelphia (Ph)-negative MPNs over the Egyptian population. Results We have tested 60 patients with Ph-negative MPNs for MPL p. W515 L/K pathological variants. Median age was 51 (22–73) years. No MPL p. W515 L/K pathological variants were detected among our patients. JAK2 p. Val617Phe in PV and PMF patients showed significantly lower frequency than other studies. Splenomegaly was significantly higher in ET patients compared to other studies. Conclusion MPL p. W515 L/K pathological variants are rare across the Egyptian Ph-negative MPNs, and further studies on a large number are recommended. MPN patients in Egypt are younger compared to different ethnic groups.

Blood Cells With Reduced Mitochondrial Membrane Potential and Cytosolic Cytochrome C Can Survive and Maintain Clonogenicity Given Appropriate Signals to Suppress Apoptosis

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4545-4553 ◽  
Author(s):  
Quan Chen ◽  
Naoshi Takeyama ◽  
Ged Brady ◽  
Alastair J.M. Watson ◽  
Caroline Dive
Keyword(s):  
Membrane Potential ◽  
Cytochrome C ◽  
Mitochondrial Membrane Potential ◽  
Blood Cells ◽  
Mitochondrial Membrane ◽  
Mitochondrial Cytochrome ◽  
Abl Tyrosine Kinase ◽  
Key Events ◽  
Cytosolic Cytochrome ◽  
Mitochondrial Cytochrome C

Reduction of mitochondrial membrane potential (Ψm) and release of cytochrome c from mitochondria appear to be key events during apoptosis. Apoptosis was induced in IC.DP premast cells by the withdrawal of interleukin-3 (IL-3). Ψm decreased by 12 hours and cytochrome c was detected in the cytosol at 18 hours. Despite these changes in the mitochondria after 18 hours of IL-3 deprivation, clonogenicity was unaffected when IL-3 was replenished at 18 hours. Activation of v-Abl tyrosine kinase (v-Abl TK) in IC.DP cells before IL-3 depletion led to increased levels of Bcl-XL, prevented reduction of Ψm and the release of mitochondrial cytochrome c, and suppressed apoptosis. Activation of v-Abl TK 18 hours after withdrawal of IL-3 when ≤10% of the cells had died restored Ψm in the remaining cells. More than 40% of cells thus rescued by v-Abl TK between 18 and 42 hours could subsequently form colonies in the presence of IL-3. These data suggest that reduction in Ψm precedes loss of mitochondrial cytochrome c in IC.DP cells; that v-Abl TK activation, probably via upregulation of Bcl-XL, prevents loss of Ψm and blocks the release of cytochrome c from mitochondria; and that neither of these mitochondrial events is sufficient for commitment to apoptosis.

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