Expression of MAC‐1 (CD11b) in acute myeloid leukemia (AML) is associated with an unfavorable prognosis

Graf, Michaela; Reif, Susanne; Kröll, Tanja; Hecht, Karin; Nuessler, V.; Schmetzer, Helga

doi:10.1002/ajh.20526

Cited by 34 publications

(19 citation statements)

References 22 publications

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“…In AML and MDS, either the level of differentiation, the frequency of CD11b + blasts, or the expression of PD-1 ligands have been described as critical factors that associate with disease progression and limit the benefit from cancer therapy 2,28,38 . Blockade of PD-1 and PD-L1 molecules has been recognized as a promising approach for cancer immunotherapy 9 ; however, to date, the efficacy of checkpoint inhibitors in myeloproliferative diseases is not clear.…”

Section: Discussionmentioning

confidence: 99%

Myeloid maturation potentiates STAT3-mediated atypical IFN-γ signaling and upregulation of PD-1 ligands in AML and MDS

Yöyen-Ermiş

Tunalı

Tavukçuoğlu

et al. 2019

Sci Rep

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Interferon (IFN)-γ is the major mediator of anti-tumor immune responses; nevertheless, cancer cells use intrigue strategies to alter IFN-γ signaling and avoid elimination. Understanding the immune regulatory mechanisms employed by acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells upon exposure to IFN-γ is critical for development of immunotherapy and checkpoint blockade therapy approaches. This study aims to explore the influence of myeloid maturation on IFN-γ-induced PD-L1 and PD-L2 expression and on pro-leukemogenic transcription factor STAT3 signaling in AML and MDS. Stimulation of myeloid blasts’ maturation by all-trans retinoic acid (ATRA) or 1α,25-dihydroxyvitamin D3 (vitamin D) increased the CD11b + fraction that expressed PD-1 ligands in response to IFN-γ. Intriguingly, STAT3 pathway was potently induced by IFN-γ and strengthened upon prolonged exposure. Nonetheless, STAT3-mediated atypical IFN-γ signaling appeared as a negligible factor for PD-L1 and PD-L2 expression. These negative influences of IFN-γ could be alleviated by a small-molecule inhibitor of STAT3, stattic, which also inhibited the upregulation of PD-L1. In conclusion, induction of myeloid maturation enhances the responsiveness of AML and MDS cells to IFN-γ. However, these malignant myeloid cells can exploit both STAT3 pathway and PD-1 ligands to survive IFN-γ-mediated immunity and maintain secondary immune resistance.

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Section: Discussionmentioning

confidence: 99%

Myeloid maturation potentiates STAT3-mediated atypical IFN-γ signaling and upregulation of PD-1 ligands in AML and MDS

Yöyen-Ermiş

Tunalı

Tavukçuoğlu

et al. 2019

Sci Rep

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“…42,43 Interestingly, several studies reported that the expression of Mac-1 in AML is associated with a poor prognosis, 42,44 which might be, at least in part, caused by Mac-1-mediated activation of the proproliferative Syk/STAT3/ STAT5 pathways.…”

Section: Discussionmentioning

confidence: 99%

β2 integrin–derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis

Oellerich

Engelke

et al. 2013

Blood

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Key Points• Integrin signaling promotes proliferative signals in AML cells that are mediated by the kinase Syk and the transcription factors STAT3 and STAT5.Spleen tyrosine kinase (Syk) induces cell survival and proliferation in a high proportion of acute myeloid leukemia (AML) blasts, but the underlying molecular events of Syk signaling have not been investigated. Proteomic techniques have allowed us to identify the multiprotein complex that is nucleated by constitutively active Syk in AML cells. This complex differs from the B-lymphoid Syk interactome with respect to several proteins, especially the integrin receptor Mac-1, the Fc-g receptor I (FcgRI), and the transcription factors STAT3 and STAT5. We show in several AML cell line models that tonic signals derived from the Fc-g chain lead to Syk-dependent activation of STAT3 and STAT5, which in turn induces cell survival and proliferation. Moreover, stimulation of Mac-1 or FcgRI intensifies the constitutive Syk-mediated STAT3/5 activation in AML cells, a scenario likely to take place in the bone marrow niche. In accordance with these findings, we observed that b 2 integrins, including Mac-1, trigger proliferation of AML cells in an AML cell/stroma coculture model. Taken together, we identified an oncogenic integrin/Syk/STAT3/5 signaling axis that might serve as a therapeutic target of AML in the future. (Blood. 2013;121(19):3889-3899)

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“…Since CD11b is present on the suppressor subpopulation of CD8 1 cells, but not on the cytotoxic subpopulation, anti-CD11b monoclonal antibodies have also been used to differentiate these populations. In AML, CD11b expression has been reported as an unfavorable prognostic indicator (241).…”

Section: Myeloid Antigensmentioning

confidence: 99%

Bone marrow aspirate and biopsy: a pathologist's perspective. II. interpretation of the bone marrow aspirate and biopsy

Riley

Williams

Ross

et al. 2009

Clinical Laboratory Analysis

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Bone marrow examination has become increasingly important for the diagnosis and treatment of hematologic and other illnesses. Morphologic evaluation of the bone marrow aspirate and biopsy has recently been supplemented by increasingly sophisticated ancillary assays, including immunocytochemistry, cytogenetic analysis, flow cytometry, and molecular assays. With our rapidly expanding knowledge of the clinical and biologic diversity of leukemia and other hematologic neoplasms, and an increasing variety of therapeutic options, the bone marrow examination has became more critical for therapeutic monitoring and planning optimal therapy. Sensitive molecular techniques, in vitro drug sensitivity testing, and a number of other special assays are available to provide valuable data to assist these endeavors. Fortunately, improvements in bone marrow aspirate and needle technology has made the procurement of adequate specimens more reliable and efficient, while the use of conscious sedation has improved patient comfort. The procurement of bone marrow specimens was reviewed in the first part of this series. This paper specifically addresses the diagnostic interpretation of bone marrow specimens and the use of ancillary techniques.

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Expression of MAC‐1 (CD11b) in acute myeloid leukemia (AML) is associated with an unfavorable prognosis

Cited by 34 publications

References 22 publications

Myeloid maturation potentiates STAT3-mediated atypical IFN-γ signaling and upregulation of PD-1 ligands in AML and MDS

Myeloid maturation potentiates STAT3-mediated atypical IFN-γ signaling and upregulation of PD-1 ligands in AML and MDS

β2 integrin–derived signals induce cell survival and proliferation of AML blasts by activating a Syk/STAT signaling axis

Bone marrow aspirate and biopsy: a pathologist's perspective. II. interpretation of the bone marrow aspirate and biopsy

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