Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors

Abstract

The myelodysplastic syndromes (MDSs) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias as a result of ineffective hematopoiesis. Development of effective treatments has been impeded by limited insights into any unifying pathogenic pathways. We provide evidence that the p38 MAP kinase is constitutively activated or phosphorylated in MDS bone marrows. Such activation is uniformly IntroductionThe myelodysplastic syndromes (MDSs) comprise a spectrum of stem-cell malignancies characterized by cytologic dysplasia and ineffective hematopoiesis. [1][2][3] Although approximately one third of patients may experience progression to acute leukemia, refractory cytopenias are the principal cause of morbidity and mortality. MDS can be divided into low-and high-risk subtypes using the International Prognostic Scoring System (IPSS), based on features such as the number of hematopoietic deficits, the percentage of marrow blasts, and cytogenetic pattern. 4 Approximately two thirds of patients present with lower-risk disease (Low and Int-1 IPSS scores) characterized by increased rates of apoptosis in the progenitor and differentiated cell compartments in the marrow. [5][6][7][8] High intramedullary apoptosis leads to ineffective hematopoiesis and peripheral cytopenias. Higher grade or more advanced disease categories (Int-2 and High IPSS scores) are associated with a significant risk of leukemia transformation with a corresponding lower apoptotic index and higher percentage of marrow blasts.Cytokines play important roles in the regulation of normal hematopoiesis, and a balance between the actions of hematopoietic growth factors and myelosuppressive factors is required for optimal production of different hematopoietic-cell lineages. Excess production of inhibitory cytokines contributes in part to ineffective hematopoiesis in MDS. Tumor necrosis factor-␣ (TNF␣) has been implicated in the increased stem-cell apoptosis seen in MDS, 9,10 and high expression of TNF receptors and TNF mRNA have been reported in MDS bone marrows. [11][12][13][14] Transforming growth factor-␤ (TGF␤), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and interferon (IFN-␥ and -␣) are also myelosuppressive, and these proinflammatory cytokines have been found to be elevated in serum of patients with MDS in various studies and are hypothesized to play a role in suppressing hematopoiesis in this disease. 9,11,[15][16][17] Because multiple cytokines are involved in promoting abnormal hematopoietic development in MDS, targeting one single cytokine may not yield appreciable clinical benefit. In fact, anti-TNF therapeutic strategies (monoclonal antibodies and TNFR blockers) have only shown minimal efficacy. [18][19][20][21] Thus, it is imperative to identify common targetable pathways that regulate many different cytokines. Our previous studies have shown that myelosuppressive cytokines such as interferons (IFN-␣, -␤, and -␥), TGF␤, and TNF␣ can all activate the p38 mitogen activated protein kinase (MAPK) in ...

Ectopic expression of C/EBP and ID1 is sufficient to restore defective neutrophil development in low-risk myelodysplasia

“…Inhibition of p38MAPK activity was found to decrease apoptosis and stimulate GM colony formation in primary MDS progenitors, suggesting a role for p38MAPK in the pathogenesis of this syndrome. 37,27 However, our data indicate that inhibition of p38MAPK is not sufficient to restore final maturation or improve the clonogenic capacity of low-risk MDS hematopoietic progenitors ( Figure 3D, 3E). Moreover, CD34 + cells from low-risk MDS patients did not show elevated levels of phosphorylated p38MAPK compared to control cells ( Figure 3A, 3B).…”

“…27 Inhibition of p38MAPK activity resulted in decreased apoptosis and stimulated colony formation of primary MDS progenitors, indicating a role for p38MAPK in the pathogenesis of MDS. 27 To determine whether aberrant p38MAPK activation may be involved in the defective neutrophil differentiation observed in MDS primary progenitors, CD34…”

Hematopoietic Stem Cell Injury Induced by Ionizing Radiation

“…In addition, activation of p38 has been implicated in BM suppression in various pathological conditions, including aplastic anemia and myelodysplastic syndromes (118,175). Furthermore, recently, it was shown that mutation of the ATM gene and knockout of the FoxO3 gene induced premature senescence/exhaustion of HSCs (69,112,149).…”

p38 MAP Kinase Regulates Stem Cell Apoptosis in Human Hematopoietic Failure

“…Patients with other causes of anemia did not reveal activation. 33 Histological examination revealed that p38 was activated in hematopoietic progenitors of all three lineages. Immunohistochemical staining with an antibody against p38 MAPK revealed no significant differences between diseased samples and controls suggesting that p38 MAPK is overactivated but not overexpressed in MDS.…”