Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia

Rombouts, Elwin; Pavic, Biljana; Löwenberg, Bob; Ploemacher, Rob E.

doi:10.1182/blood-2004-02-0566

Cited by 253 publications

(206 citation statements)

References 40 publications

(33 reference statements)

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“…AMLs with high CXCR4 cell surface expression, and with, therefore, a high tendency of stromal protection, have been shown to have a poor prognosis. 22,23 Inhibition of CXCR4 has been able to overcome resistance to numerous drugs. 24,25 CXCR4 inhibitors that target the stromal interaction and release the leukemic cells from the microenvironment have both a mobilizing and cell-cycle activating effect upon leukemic cells and may sensitize AML for chemotherapeutic cell killing.…”

Section: Discussionmentioning

confidence: 99%

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

Thomas

Raffoux

Renneville

et al. 2010

Cancer

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BACKGROUND:Priming with granulocytic hematopoietic growth factors may modulate cell cycle kinetics of leukemic cells and render them more susceptible to phase‐specific chemotherapeutic agents. In a first report, we have shown that priming with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) may enhance complete remission (CR) rate and event‐free survival (EFS) in younger adults with acute myeloid leukemia (AML).METHODS:In this randomized trial, 259 patients with AML were randomized at baseline to receive or not receive GM‐CSF concurrently with all cycles of chemotherapy. The effects of GM‐CSF on survival were reported herein with a long‐term follow‐up and studied according to distinct biological subgroups defined on cytogenetics and molecular markers.RESULTS:The EFS rate was better in the GM‐CSF group (43% vs 34%; P = .04). GM‐CSF did not improve the outcome in patients from good risk subgroups, while patients from poor risk subgroups benefited from GM‐CSF therapy. In this population, the difference in terms of EFS probability was mainly observed in patients with high initial white blood cell count and in those with FLT3‐ITD or MLL rearrangement. When combining these 2 molecular abnormalities for comparison of the effect of GM‐CSF priming, the difference in terms of EFS was highly significant (5‐year EFS, 39% with GM‐CSF vs 8% without GM‐CSF; P = .007).CONCLUSIONS:Sensitization of leukemic cells and their progenitors by GM‐CSF appears as a plausible strategy for improving the outcome of patients with newly diagnosed AML. Patients with poor‐prognosis FLT3‐ITD or MLL rearrangement might be a good target population to further investigate priming strategies. Cancer 2010. © 2010 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

Thomas

Raffoux

Renneville

et al. 2010

Cancer

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“…113 This function of CXCR4 could explain why CXCR4 surface expression on AML cells has such a profound negative prognostic impact in AML. [114][115][116] Plerixafor is currently used in an ongoing clinical trial for mobilization of AML cells from the protective marrow microenvironment to the blood, where the AML cells are then targeted by conventional cytotoxic drugs. The feasibility of using Plerixafor for AML cell mobilization to the blood in an animal model and in AML patients on this trial was recently reported.…”

Section: Acute Myeloid Leukemiamentioning

confidence: 99%

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Burger

Peled²

2008

Leukemia

414

316

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“…CXCR4 expression on AML cells is implicated as a prognostic marker in the disease (13,14). To explore potential prognostic value of CXCR4 + microparticles and SDF-1 in AML, we examined the correlation between their levels detected by ELISA and circulating WBC count.…”

Section: Resultsmentioning

confidence: 99%

“…Yet, primary AML cells maintain many characteristics of normal hematopoietic precursors, such as CXCR4 expression, response to SDF-1 in vitro, and egress into the circulation in transplanted NOD/SCID mice (9)(10)(11)(12). Association of SDF-1/CXCR4 with AML pathogenesis was indicated in two recent studies in which levels of CXCR4 expression on CD34 + cells were found as a negative predictor of overall survival and relapse-free survival (13,14). However, conflicting results have been described by others (15,16).…”

Section: Introductionmentioning

confidence: 99%

Functional CXCR4-Expressing Microparticles and SDF-1 Correlate with Circulating Acute Myelogenous Leukemia Cells

et al. 2006

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Stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 are implicated in the pathogenesis and prognosis of acute myelogenous leukemia (AML). Cellular microparticles, submicron vesicles shed from the plasma membrane of various cells, are also associated with human pathology. In the present study, we investigated the putative relationships between the SDF-1/CXCR4 axis and microparticles in AML. We detected CXCR4-expressing microparticles (CXCR4 + microparticles) in the peripheral blood and bone marrow plasma samples of normal donors and newly diagnosed adult AML patients. In samples from AML patients, levels of CXCR4 + microparticles and total SDF-1 were elevated compared with normal individuals. The majority of CXCR4 + microparticles in AML patients were CD45 + , whereas in normal individuals, they were mostly CD41 + . Importantly, we found a strong correlation between the levels of CXCR4 + microparticle and WBC count in the peripheral blood and bone marrow plasma obtained from the AML patients. Of interest, levels of functional, noncleaved SDF-1 were reduced in these patients compared with normal individuals and also strongly correlated with the WBC count. Furthermore, our data indicate NH 2 -terminal truncation of the CXCR4 molecule in the microparticles of AML patients. However, such microparticles were capable of transferring the CXCR4 molecule to AML-derived HL-60 cells, enhancing their migration to SDF-1 in vitro and increasing their homing to the bone marrow of irradiated NOD/SCID/B2m null mice. The CXCR4 antagonist AMD3100 reduced these effects. Our findings suggest that functional CXCR4 + microparticles and SDF-1 are involved in the progression of AML. We propose that their levels are potentially valuable as an additional

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Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia

Cited by 253 publications

References 40 publications

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long‐term analysis of the ALFA‐9802 GM‐CSF study

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

Functional CXCR4-Expressing Microparticles and SDF-1 Correlate with Circulating Acute Myelogenous Leukemia Cells

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