Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases

Xu, Mingjiang; Bruno, Edward; Chao, Joseph; Huang, Stephen; Finazzi, Guido; Fruchtman, Steven; Popat, Uday; Prchal, Josef T.; Barosi, Giovanni; Hoffman, Ronald

doi:10.1182/blood-2004-08-3238

Cited by 101 publications

(115 citation statements)

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“…It has been suggested that it may be due to increased cleavage of the extracellular domain of CXCR4 because of the proteolytic environment created by the pathological neutrophil emperipolesis within the megakaryocytes 15 . In this context, the normal levels of CXCR4 expressed by the megakaryocytes present in the marrow of Gata1 low mice are of interest.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, anatomical abnormalities may not be sufficient to alter the balance of events that result in the retention of stem/progenitor cells within the marrow. Other parameters, such as changes in chemokine levels 10,[12][13][14] and/or disruption of adhesive interactions favoring retention of stem/progenitor cells within the marrow 15 , may be operational.…”

Section: Introductionmentioning

confidence: 99%

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Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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Objective-To assess whether alterations in the SDF-1/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1 low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking.Materials and Methods-In the mouse, SDF-1 mRNA levels were assayed in liver, spleen and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients.Results-In Gata1 low mice, the plasma SDF-1 protein was 5-times higher than normal in younger animals. Furthermore, SDF-1 immuno-staining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, the plasma SDF-1 levels in PMF patients were significantly higher (by 2-fold) than normal (p<0.01) and SDF-1 immuno-staining of marrow biopsiy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similarly to what already has been reported for PMF patients, the marrow from Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Gata1 low mice contained fewer CXCR4 pos CD117 pos cells and these cells expressed low levels of CXCR4 mRNA and protein. NIH Public AccessConclusion-Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1 low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Migliaccio

Martelli

Verrucci

et al. 2008

Experimental Hematology

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“…15,18 The percentage of cells migrating was calculated by determining the ratio of the number of cells recovered from the lower compartment to the total number of cells loaded in the upper compartment. Migrating cells were also assayed in semisolid media for their ability to form hematopoietic colonies and those colonies were plucked and their JAK2 status determined.…”

Section: Migration Assaymentioning

confidence: 99%

Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells

Wang

Zhang

Tripodi

et al. 2010

Blood

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IntroductionPrimary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN), which is thought to originate at the level of a pluripotent hematopoietic stem cell (HSC). 1-5 A gain-of-function mutation JAK2V617F has been identified in the MPNs, which is present in the granulocytes of approximately 95% of patients with polycythemia vera and 50% of patients with either PMF or essential thrombocythemia. In approximately 10% of patients with JAK2V617F-negative PMF, an additional somatic mutation of the thrombopoietin receptor gene MPL has also been identified. 6 Furthermore, malignant clones harboring additional genetic abnormalities including the TET oncogene family member 2 (TET2), the additional sex combs like gene and the gene for isocitrate dehydrogenase 1 as well as characteristic cytogenetic abnormalities have been observed in PMF indicating that multiple genetic events are likely responsible for the origins of this MPN. 7 Epigenetic modifications leading to the dysregulation of critical genes that contribute to cell proliferation, differentiation, cell death, and trafficking have also been thought to play a role in the origins of PMF. [8][9] Mutations in TET2, for instance, might contribute to the origins of PMF by altering chromatin structure. TET1 affects the conversion of 5-methylcytosine to 5-hydroxymethylcytosine and therefore influences epigenetic regulation of transcription. 10 Previously we had reported that the constitutive mobilization of cluster of differentiation (CD)34 ϩ cells in PMF could be accounted by in part by the reduced expression of chemokine (C-X-C motif) receptor (CXCR)4 by PMF CD34 ϩ cells which has been attributed to hypermethylation of its promoter. 11 In addition, we have reported that the sequential treatment of PMF CD34 ϩ cells with a DNA methyltransferase inhibitor, 5-aza-2Ј-deoxycytidine (5azaD), followed by an histone deacetylase (HDAC) inhibitor (HDACI), trichostatin A (TSA), resulted in an up-regulation of CXCR4 expression by PMF CD34 ϩ cells leading to correction of the abnormal cellular trafficking characteristic of PMF as well as a reduction of the burden of malignant hematopoietic progenitor cells (HPCs). 12,13 These preclinical studies illustrate the profound effects of chromatin-modifying agents (CMAs) on PMF HPCs and led us to further evaluate these strategies, this time using drugs that are currently approved for the treatment of other hematologic malignancies, and to determine whether they affect malignant stem cells.We hypothesize that curative drug therapies for PMF would ideally eliminate or at least reduce the burden of PMF HSCs/ HPCs, allowing their normal counterparts to predominate. Currently, the standard surrogate assay for human HSCs assesses the ability of a putative HSC population to establish hematopoiesis in immunodeficient mice. In this report, we provide evidence that sequential treatment with 5azaD followed by the HDACI, suberoylanilide hydroxamic acid (SAHA), affects not only PMF HPCs but also stem cells. Sequential treatment with CMAs therefor...

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“…104 The release of CD34( þ ) cells is generally due to a combination of increased levels of proteases 105 and especially due to the downregulation of the CXCR4 receptor on CD34( þ ) cells. 106 An altered SDF-1/CXCR4 axis was demonstrated in PMF patients with CD34( þ ) cells in the periphery.…”

Section: Spotlightmentioning

confidence: 99%

Aberrant signal transduction pathways in myeloproliferative neoplasms

2008

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The BCR-ABL-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), entered the spotlight in 2005 when the unique somatic acquired JAK2 V617F mutation was described in 495% of PV and in 50% of ET and PMF patients. For the very rare PV patients who do not harbor the JAK2 V617F mutation, exon 12 JAK2 mutants were discovered also to result in activated forms of JAK2. A minority of ET and PMF patients harbor mutations that constitutively activate the thrombopoietin receptor (TpoR). In bone marrow reconstitution models based on retroviral transduction, the phenotype induced by JAK2 V617F is less severe and different from the rapid fatal myelofibrosis induced by TpoR W515L. The reasons for these differences are unknown. Exactly by which mechanism(s) one acquired somatic mutation, JAK2 V617F, can promote three different diseases remains a mystery, although gene dosage and host genetic variation might have important functions. We review the recent progress made in deciphering signaling anomalies in PV, ET and PMF, with an emphasis on the relationship between JAK2 V617F and cytokine receptor signaling and on cross-talk with several other signaling pathways.

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Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases

Abstract: Idiopathic myelofibrosis (IM) is characterized by increased numbers of CD34

Cited by 101 publications

References 50 publications

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells

Aberrant signal transduction pathways in myeloproliferative neoplasms

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