Endogenous FLT-3 ligand serum levels are associated with disease stage in patients with myelodysplastic syndromes

Zwierzina, Heinz; Anderson, Joseph C.; Rollinger-Holzinger, Ingrid; Torok‐Storb, Beverly; Nuessler, V.; Lyman, S D

doi:10.1038/sj.leu.2401378

Cited by 21 publications

(15 citation statements)

References 30 publications

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“…Not only combinations of cytokines are important but also the concentration of each cytokine in the culture is an important determinant of HSC fate. This notion was derived from the in vivo observation, where FL3 serum levels were dysregulated in leukemic patients those received HSCT [111]. Ex vivo studies showed that negative impact of IL-3 on HSC expansion was alleviated at high concentration of FL and SCF cytokines and modulation of concentration of cytokines significantly enhanced the proliferation more than 50-fold for LT-HSCs and 500-fold for colony forming units (CFUs) [112].…”

Section: Ex Vivo Expansion Of Hscmentioning

confidence: 99%

Hematopoietic Stem Cells: Transcriptional Regulation, Ex Vivo Expansion and Clinical Application

Aggarwal¹,

Lu²,

Pompili³

et al. 2012

CMM

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Maintenance of ex vivo hematopoietic stem cells (HSC) pool and its differentiated progeny is regulated by complex network of transcriptional factors, cell cycle proteins, extracellular matrix, and their microenvironment through an orchestrated fashion. Strides have been made to understand the mechanisms regulating in vivo quiescence and proliferation of HSCs to develop strategies for ex vivo expansion. Ex vivo expansion of HSCs is important to procure sufficient number of stem cells and as easily available source for HSC transplants for patients suffering from hematological disorders and malignancies. Our lab has established a nanofiber-based ex vivo expansion strategy for HSCs, while preserving their stem cell characteristics. Ex vivo expanded cells were also found biologically functional in various disease models. However, the therapeutic potential of expanded stem cells at clinical level still needs to be verified. This review outlines transcriptional factors that regulate development of HSCs and their commitment, genes that regulate cell cycle status, studies that attempt to develop an effective and efficient protocol for ex vivo expansion of HSCs and application of HSC in various non-malignant and malignant disorders. Overall the goal of the current review is to deliver an understanding of factors that are critical in resolving the challenges that limit the expansion of HSCs in vivo and ex vivo.

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Section: Ex Vivo Expansion Of Hscmentioning

confidence: 99%

Hematopoietic Stem Cells: Transcriptional Regulation, Ex Vivo Expansion and Clinical Application

Aggarwal¹,

Lu²,

Pompili³

et al. 2012

CMM

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“…In MDS, the bone marrow comprises cells originating from both the normal and abnormal, transformed clones [87,88]. Cytokines are highly expressed by stromal and mononuclear cells of MDS patients and, in contrast to normal subjects, are present in serum concentrations sufficient for stimulating both normal and abnormal hematopoiesis [89][90][91][92][93][94][95]. Serum concentrations of TPO and FL, in fact, were observed to correlate with disease stage in MDS patients [94,95].…”

Section: Myelodysplastic Syndromes (Mds)mentioning

confidence: 99%

Leukemic cells and the cytokine patchwork

Kiss

Benkö

Kovács

2003

Pediatric Blood & Cancer

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“…19,20 Furthermore, it has previously been shown that plasma FL levels rise during periods of bone marrow aplasia induced by chemotherapy or radiation. [21][22][23][24][25][26][27] Given that in both of these trials lestaurtinib was administered after intensive chemotherapy, we decided to examine FL levels in the plasma samples available to us. To derive an estimate of FL levels in newly diagnosed AML patients, we tested plasma from 7 consecutive AML patients presenting to our institution at diagnosis.…”

mentioning

confidence: 99%

FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo

Sato

Yang

Knapper

et al. 2011

Blood

225

252

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We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated IntroductionAcute myeloid leukemia (AML) patients who harbor the FLT3/ITD mutation have an exceptionally poor prognosis. 1,2 During the past decade, efforts have been underway to develop FLT3 inhibitors in the hopes of improving outcomes for these patients. 3 Several agents have now been studied as monotherapy for this disease, and the results have been only modestly successful. Although there have been a few remissions reported, the responses are usually limited to clearance of peripheral blasts, with persistence of disease in the marrow. In light of this, attention has turned to incorporating these agents into existing chemotherapy regimens, on the hypothesis that FLT3 inhibition will synergize with chemotherapy in inducing cytotoxicity. 4 Alternately, others have postulated that mobilizing the leukemia cells from the marrow might enhance the efficacy of FLT3 inhibition and have therefore tested FLT3 inhibitors in combination with CXCR4 inhibition. 5 Several large trials of chemotherapy administered in combination with FLT3 inhibitors are either actively accruing or have recently completed accrual. Because chemotherapy may alter the pharmacokinetics of FLT3 inhibitors and therefore affect target inhibition in vivo, we examined FLT3 inhibition in patients receiving lestaurtinib, an indolocarbazole FLT3 inhibitor, from 2 separate trials in which the agent was combined with chemotherapy. We noted a discrepancy in the degree of FLT3 inhibition, as measured by a plasma inhibitory activity assay, between the 2 groups of patients. We hypothesized that high levels of FLT3 ligand (FL), a cytokine that is known to increase after myelosuppressive therapy, could be interfering with FLT3 inhibition in these trials. We have therefore examined FL levels in response to chemotherapy and FLT3 inhibition, as well as the effect of FL levels on the efficacy of FLT3 inhibitors in vitro and in vivo. Our findings may explain why blasts in the bone marrow are more resistant to FLT3 inhibitors and furthermore have important implications both for FLT3 mutant AML as a disease as well as for efforts to incorporate FLT3 inhibitors into AML therapy. Methods ...

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Endogenous FLT-3 ligand serum levels are associated with disease stage in patients with myelodysplastic syndromes

Cited by 21 publications

References 30 publications

Hematopoietic Stem Cells: Transcriptional Regulation, Ex Vivo Expansion and Clinical Application

Hematopoietic Stem Cells: Transcriptional Regulation, Ex Vivo Expansion and Clinical Application

Leukemic cells and the cytokine patchwork

FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo

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