title: GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia.
abstract: 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.
authors: Department of Hematologic Malignancies, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. eric.padron@moffitt.org
authors: Eric
authors: E
authors: Padron
authors: Jeffrey S
authors: JS
authors: Painter
authors: Sateesh
authors: S
authors: Kunigal
authors: Adam W
authors: AW
authors: Mailloux
authors: Kathy
authors: K
authors: McGraw
authors: Jessica M
authors: JM
authors: McDaniel
authors: Eunhee
authors: E
authors: Kim
authors: Christopher
authors: C
authors: Bebbington
authors: Mark
authors: M
authors: Baer
authors: Geoffrey
authors: G
authors: Yarranton
authors: Jeffrey
authors: J
authors: Lancet
authors: Rami S
authors: RS
authors: Komrokji
authors: Omar
authors: O
authors: Abdel-Wahab
authors: Alan F
authors: AF
authors: List
authors: Pearlie K
authors: PK
authors: Epling-Burnette
mesh_terms: D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000378:metabolism*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D050799:STAT5 Transcription Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
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