‘Low‐risk’ myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro‐ versus anti‐apoptotic bcl‐2‐related proteins

Parker, Jane E.; Fishlock, Keith; Mijović, Aleksandar; Czepulkowski, Barbara; Pagliuca, Antonio; Mufti, Ghulam J.

doi:10.1046/j.1365-2141.1998.01114.x

Cited by 105 publications

(76 citation statements)

References 27 publications

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“…Other investigators have also reported that apoptosis was mainly seen in immature CD34+ progenitors, after separation of marrow cells into CD34+ and CD34− cell fractions [6,11,27]. The fact that apoptosis in the FAB low-risk group was higher than that in the FAB high-risk group, although not significantly different, is in accordance with a number of previous studies [1,6,10,11,25,28]. The increased apoptosis observed in "early" MDS is possibly a physiological mechanism whereby the hematopoietic system is able to eliminate potentially harmful Fig.…”

Section: Discussionmentioning

confidence: 87%

“…Indeed, a study using annexin V method co-staining with CD34, showed increased annexin V binding in CD34+ cells in MDS [26]. Other investigators have also reported that apoptosis was mainly seen in immature CD34+ progenitors, after separation of marrow cells into CD34+ and CD34− cell fractions [6,11,27]. The fact that apoptosis in the FAB low-risk group was higher than that in the FAB high-risk group, although not significantly different, is in accordance with a number of previous studies [1,6,10,11,25,28].…”

Section: Discussionmentioning

confidence: 94%

“…The initial peak corresponds to cells at the Go/G1 phase, the valley following represents S phase cells, whereas the second, lower peak refers to G2/ M cells clones. It is a kind of homeostatic process in order to control cell numbers [6].…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis is a physiological mechanism whereby the hematopoietic system is able to eliminate potentially harmful clones. It is a kind of homeostatic process in order to control cell numbers [6]. Lower p21 expression in patients could also be explained through the suppression of the apoptotic pathway that characterizes patients compared to healthy donors.…”

Section: Discussionmentioning

confidence: 99%

“…Almost one third of the bone marrow cells of MDS patients are engaged in DNA synthesis [4][5][6][7][8]. The increased rate of cell birth is canceled by an equally increased rate of cell death resulting in peripheral cytopenias.…”

Section: Introductionmentioning

confidence: 99%

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Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

et al. 2009

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

et al. 2009

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The Myelodysplastic Syndrome

Silverman

2017

Holland‐Frei Cancer Medicine

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Overview The existence of a hematopoietic disorder characterized by anemia and dyspoiesis preceding the onset of acute myelocytic leukemia (AML) has been recognized since the early part of the twentieth century. Initially designated as preleukemia, the syndrome was ill defined and could only be established with certainty retrospectively. Moreover, the terminology itself conveyed an unwarranted confidence in predicting the outcome that often belied the facts. The more accurately descriptive and appropriate designation as a myelodysplastic syndrome (MDS) was adopted in 1976 by the French–American–British (FAB) study group. The FAB classification permitted the prospective identification of patients within this heterogeneous clonal disorder. MDS, derived from a multipotent hematopoietic stem cell, is characterized clinically by a hyperproliferative bone marrow, reflective of ineffective hematopoiesis, and is accompanied by one or more peripheral blood cytopenias. Bone marrow failure results, leading to death from bleeding and infection in the majority, while transformation to acute leukemia occurs in up to 40% of patients. The evolution of the disease proceeds in accordance with the multistep pathogenesis theory of carcinogenesis and can thus serve as an important model in furthering our understanding of the processes involved in neoplastic transformation. This constellation of findings raises the question of whether MDS represents a frank neoplastic state or is merely a preneoplastic condition in transition. The syndrome appears to represent a spectrum where the initial lesion in the genome, though clinically undetectable, subsequently evolves, with the acquisition of additional genetic and epigenetic lesions, to a state of frank neoplasia. The designation of this disorder as an MDS, rather than preleukemia, permits its distinction from other abnormalities that are known to be associated with the development of acute leukemia. These latter include the classic myeloproliferative syndromes (polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, essential thrombocythemia), aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), as well as Fanconi, Bloom, and Down syndromes. These particular “preleukemic states” are beyond the scope of this chapter. MDS can be further divided into primary and secondary syndromes. The former arise de novo and are of indeterminate etiology, while the latter are induced by identifiable environmental, occupational, or iatrogenic causes. Estimates of the incidence of MDS range from a frequency equal to that of AML or approximately 14,000 new cases per year in the United States to almost twice that of AML. The SEER database now tracks the disease; thus more accurate data will be available in the future. An estimate based on medical insurance claims indicated a total of 107,000 cases in the observation period from 2009 through 2011. The consensus is that the incidence is increasing owing to a number of factors, including greater awareness, greater diagnostic precision, and the aging of the population.

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Expression and prognostic significance of Bcl‐2 family proteins in myelodysplastic syndromes

Boudard¹,

Vasselon

Bertheas

et al. 2002

American J Hematol

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Excessive apoptosis is implicated in the pathogenesis of myelodysplastic syndromes (MDS). We assessed by flow cytometry the expression of several members of the Bcl-2 family in bone marrow mononuclear cells (BMMNC) of 168 MDS samples at diagnosis. The proteins studied were Bcl-2, Bcl-xL (anti-apoptotic), Bax, Bad, Bak, and Bcl-xS (pro-apoptotic). The percentage of BMMNC expressing Bcl-2 and Bcl-xL was higher in refractory anemia with excess of blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML) than in refractory anemia (RA) and RA with ringed sideroblasts (RAS). Conversely pro-apoptotic proteins Bad, Bak, and Bcl-xS were detected in a higher percentage of cells in RA and RAS. RA and RAS were associated with an increased Bcl-xS/Bcl-xL ratio. The expression of anti-apoptotic proteins was also correlated with that of CD34 and P170 and with the percentage of blast cells. Two-color analyses demonstrated that CD34 and Bcl-2 were usually expressed in the same cells. No significant correlation was found with cytogenetic abnormalities. Higher expression of pro-apoptotic Bcl-2-family proteins (Bak, Bad, Bcl-xS) and higher Bcl-xS/Bcl-xL ratio were associated with longer survival and decreased risk of leukemic transformation in univariate analysis, whereas expression of anti-apoptotic proteins was associated with decreased survival. Consequently Bcl-2 proteins expression was well correlated with the International Prognostic Scoring System (IPSS). Our data confirm that the control of apoptosis is deregulated in MDS cells. Moreover, the study of markers such as CD34 (or Bcl-2), Bcl-xL, and Bcl-xS provides additional prognostic information.

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‘Low‐risk’ myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro‐ versus anti‐apoptotic bcl‐2‐related proteins

Cited by 105 publications

References 27 publications

Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

Cell cycle and apoptosis regulatory gene expression in the bone marrow of patients with de novo myelodysplastic syndromes (MDS)

The Myelodysplastic Syndrome

Expression and prognostic significance of Bcl‐2 family proteins in myelodysplastic syndromes

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