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GM-CSF–dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia
Journal article   Open access   Peer reviewed

GM-CSF–dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia

Eric Padron, Jeffrey S. Painter, Sateesh Kunigal, Adam W. Mailloux, Kathy McGraw, Jessica M. McDaniel, Eunhee Kim, Christopher Bebbington, Mark Baer, Geoffrey Yarranton, …
Blood, Vol.121(25), pp.5068-5077
06/20/2013
DOI: 10.1182/blood-2012-10-460170
PMCID: PMC4347259
PMID: 23632888
url
https://doi.org/10.1182/blood-2012-10-460170View
Published (Version of record) Open Access

Abstract

GM-CSF–dependent STAT5 hypersensitivity is detected in 90% of CMML samples and is enhanced by signaling mutations. Treatment with a GM-CSF–neutralizing antibody and JAK2 inhibitors reveals therapeutic potential. Granulocyte-macrophage–colony-stimulating factor (GM-CSF) hypersensitivity is a hallmark of juvenile myelomonocytic leukemia (JMML) but has not been systematically shown in the related human disease chronic myelomonocytic leukemia (CMML). We find that primary CMML samples demonstrate GM-CSF–dependent hypersensitivity by hematopoietic colony formation assays and phospho-STAT5 (pSTAT5) flow cytometry compared with healthy donors. Among CMML patients, the pSTAT5 hypersensitive response positively correlated with high-risk disease, peripheral leukocytes, monocytes, and signaling-associated mutations. When compared with IL-3 and G-CSF, GM-CSF hypersensitivity was cytokine specific and thus a possible target for intervention in CMML. To explore this possibility, we treated primary CMML cells with KB003, a novel monoclonal anti–GM-CSF antibody, and JAK2 inhibitors. We found that an elevated proportion of immature GM-CSF receptor-α(R) subunit-expressing cells were present in the bone marrow myeloid compartment of CMML. In survival assays, we found that myeloid and monocytic progenitors were sensitive to GM-CSF signal inhibition. Our data indicate that a committed myeloid precursor expressing CD38 may represent the progenitor population with enhanced GM-CSF dependence in CMML, consistent with results in JMML. These preclinical data indicate that GM-CSF signaling inhibitors merit further investigation in CMML and that GM-CSFR expression on myeloid progenitors may be a biomarker for this therapy.
 Myeloid Neoplasia

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