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Purpose: Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi., Experimental Design: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and patient-derived xenograft models of disease. We used standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models., Results: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Furthermore, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy., Conclusions: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data support further clinical investigation of this combination., (©2023 American Association for Cancer Research.)

Myeloblast expansion is a hallmark of disease progression and comprises CD34+ hematopoietic stem and progenitor cells (HSPC). How this compartment evolves during disease progression in chronic myeloid neoplasms is unknown. Using single-cell RNA sequencing and high-parameter flow cytometry, we show that chronic myelomonocytic leukemia (CMML) CD34+ HSPC can be classified into three differentiation trajectories: monocytic, megakaryocyte-erythroid progenitor (MEP), and normal-like. Hallmarks of monocytic-biased trajectory were enrichment of CD120b+ inflammatory granulocyte-macrophage progenitor (GMP)-like cells, activated cytokine receptor signaling, phenotypic hematopoietic stem cell (HSC) depletion, and adverse outcomes. Cytokine receptor diversity was generally an adverse feature and elevated in CD120b+ GMPs. Hypomethylating agents decreased monocytic-biased cells in CMML patients. Given the enrichment of RAS pathway mutations in monocytic-biased cells, NRAS-competitive transplants and LPS-treated xenograft models recapitulated monocytic-biased CMML, suggesting that hematopoietic stress precipitates the monocytic-biased state. Deconvolution of HSPC compartments in other myeloid neoplasms and identifying therapeutic strategies to mitigate the monocytic-biased differentiation trajectory should be explored., Significance: Our findings establish that multiple differentiation states underlie CMML disease progression. These states are negatively augmented by inflammation and positively affected by hypomethylating agents. Furthermore, we identify HSC depletion and expansion of GMP-like cells with increased cytokine receptor diversity as a feature of myeloblast expansion in inflammatory chronic myeloid neoplasms. This article is highlighted in the In This Issue feature, p. 476., (©2022 American Association for Cancer Research.)

Purpose: Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling., Patients and Methods: A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control., Results: The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials., Conclusions: Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans. See related commentary by Shastri and Adrianzen-Herrera, p. 6069 ., (©2021 American Association for Cancer Research.)