Monocytic differentiation and AHR signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia

Abstract Introduction/Objective Histiocytic sarcoma (HS) is rare (<1% of hematolymphoid neoplasms), and can present extranodally as disseminated disease. Immunophenotypically, the cells express CD163, CD68, lysozyme and CD45. HS often occurs as a secondary event following B-cell lymphomas, acute lymphoblastic leukemia or acute myeloid leukemia (AML) typically with monocytic differentiation retaining the same molecular/cytogenetic abnormalities as the primary tumor. Results Our patient, a 47 year old male was diagnosed with myeloid sarcoma (MS) following FNA of a new neck mass. A bone marrow biopsy revealed AML without monocytic differentiation. Flow cytometric findings of both marrow and neck mass were similar (positive for CD34, CD117, CD33, CD11b, CD13, CD15, CD64, CD7; negative for CD4, CD14, CD56). Karyotypic and FLT3 ITD mutation analysis were normal. CNS involvement was diagnosed 2 months later, while a marrow biopsy (status post therapy) confirmed resolution of AML. A hypermetabolic left perinephric mass noted by PET CT, when biopsied, showed large epithelioid polygonal cells with amphophilic cytoplasm and atypical vesicular nuclei (positive for CD68, PU.1; negative for LCA, CD163, CD34, CD4, pankeratin). A diagnosis of atypical epithelioid neoplasm suggestive of HS was rendered, although negativity for LCA and CD163 was unusual. No treatment was given for HS. A month later, the patient presented with a cheek mass diagnosed again as being suggestive of HS. His AML also relapsed. Next-generation sequencing (37 genes including BRAF) from both marrow and tissue samples detected the presence of a nonsense mutation in exon 7 of WT1 (p.Ser169). Conclusion Our case appears to be the first reported one of disseminated HS preceded by MS and concomitant AML, lacking monocytic differentiation. The findings overall support the hypothesis of origin as being from a common progenitor cell differentiating along both myeloid and histiocytic/other cell lineages at different time points.

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The microRNA-26a target E2F7 sustains cell proliferation and inhibits monocytic differentiation of acute myeloid leukemia cells

Cell Death and Disease ◽

10.1038/cddis.2012.151 ◽

2012 ◽

Vol 3 (10) ◽

pp. e413-e413 ◽

Cited By ~ 41

Author(s):

B Salvatori ◽

I Iosue ◽

A Mangiavacchi ◽

G Loddo ◽

F Padula ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Leukemia Cells ◽

Monocytic Differentiation ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

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The Value of CD64 Expression in Distinguishing Acute Myeloid Leukemia With Monocytic Differentiation From Other Subtypes of Acute Myeloid Leukemia: A Flow Cytometric Analysis of 64 Cases

Archives of Pathology & Laboratory Medicine ◽

10.5858/2007-131-748-tvocei ◽

2007 ◽

Vol 131 (5) ◽

pp. 748-754

Author(s):

Cherie H. Dunphy ◽

Wohzan Tang

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Flow Cytometric Analysis ◽

World Health ◽

Monocytic Differentiation ◽

Flow Cytometric Immunophenotyping ◽

Cd64 Expression ◽

Flow Cytometric ◽

Health Organization ◽

Acute Myeloid

Abstract Context.—Flow cytometric immunophenotyping is a useful ancillary tool in the diagnosis and subclassification of acute myeloid leukemias (AMLs). A recent study concluded that CD64 is sensitive and specific for distinguishing AMLs with a monocytic component (ie, AML M4 and AML M5) from other AML subtypes. However, in that study, the intensity of CD64 was not well defined and the number of non-M4/non-M5 AMLs was small. Objective.—To evaluate the usefulness of CD64 by flow cytometric immunophenotyping in distinguishing AMLs with monocytic differentiation from other AML subtypes. Design.—Sixty-four AMLs subclassified based on the French-American-British and World Health Organization classifications on pretreatment bone marrows were retrieved from our files (7 M0s, 11 M1s, 17 M2s, 7 M3s, 9 M4s, 7 M5s, 4 M6s, and 2 M7s). A standard panel of markers, including CD2, CD3, CD5, CD7, CD10, CD11b, CD13, CD14, CD15, CD19, CD20, CD33, CD34, CD45, CD56, CD64, CD117, and HLA-DR, were analyzed by flow cytometric immunophenotyping in all AMLs (52 bone marrow samples; 12 peripheral blood samples). Results.—CD64 was expressed in AML subtypes M0 to M5 in varying intensities: heterogeneously expressed in 1 of 7 M0s; dimly expressed in 3 of 11 M1s; dimly and moderately expressed in 6 and 2 of 17 M2s, respectively; dimly and moderately expressed in 5 and 1 of 7 M3s, respectively; dimly expressed in 4 of 9 M4s; and heterogeneously, moderately, and strongly expressed in 1, 3, and 3 of 7 M5s, respectively. Conclusions.—Strong CD64 expression distinguishes AML M5; however, heterogeneous, dim, or moderate expression in itself does not distinguish M0 through M4 subtypes from M5 with dim to moderate CD64 expression. However, any CD64 expression associated with strong CD15 expression distinguishes AML M4 or M5, from other AML subtypes.

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Is Hematopoietic Stem Cell Transplantation Required to Unleash the Full Potential of Immunotherapy in Acute Myeloid Leukemia?

Journal of Clinical Medicine ◽

10.3390/jcm9020554 ◽

2020 ◽

Vol 9 (2) ◽

pp. 554 ◽

Cited By ~ 1

Author(s):

Edward Abadir ◽

Robin E. Gasiorowski ◽

Pablo A. Silveira ◽

Stephen Larsen ◽

Georgina J. Clark

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Hematologic Toxicity ◽

Full Potential ◽

Monocytic Differentiation ◽

Hematopoietic Stem ◽

Acute Myeloid

From monoclonal antibodies (mAbs) to Chimeric Antigen Receptor (CAR) T cells, immunotherapies have enhanced the efficacy of treatments against B cell malignancies. The same has not been true for Acute Myeloid Leukemia (AML). Hematologic toxicity has limited the potential of modern immunotherapies for AML at preclinical and clinical levels. Gemtuzumab Ozogamicin has demonstrated hematologic toxicity, but the challenge of preserving normal hematopoiesis has become more apparent with the development of increasingly potent immunotherapies. To date, no single surface molecule has been identified that is able to differentiate AML from Hematopoietic Stem and Progenitor Cells (HSPC). Attempts have been made to spare hematopoiesis by targeting molecules expressed only on later myeloid progenitors as well as AML or using toxins that selectively kill AML over HSPC. Other strategies include targeting aberrantly expressed lymphoid molecules or only targeting monocyte-associated proteins in AML with monocytic differentiation. Recently, some groups have accepted that stem cell transplantation is required to access potent AML immunotherapy and envision it as a rescue to avoid severe hematologic toxicity. Whether it will ever be possible to differentiate AML from HSPC using surface molecules is unclear. Unless true specific AML surface targets are discovered, stem cell transplantation could be required to harness the true potential of immunotherapy in AML.

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Results from the first-in-human study of mivebresib (ABBV-075), a pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/refractory acute myeloid leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7030 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7030-7030 ◽

Cited By ~ 5

Author(s):

Olatoyosi Odenike ◽

Johannes E. Wolff ◽

Gautam Borthakur ◽

Ibrahim Taha Aldoss ◽

David Rizzieri ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Febrile Neutropenia ◽

Myeloid Leukemia ◽

Target Genes ◽

Phase 1 ◽

Human Study ◽

Dependent Manner ◽

Bet Inhibitor ◽

Acute Myeloid

7030 Background: Bromodomain and extra-terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV-075) is a pan-BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2-part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480). Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML. Methods: Mivebresib monotherapy (MIV-mono), or combined with venetoclax (MIV-VEN), were administered daily to adult patients with AML. The dose-limiting toxicity (DLT) period was 28 d. Results: As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had > 2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-combo) and 22 who began treatment in MIV-VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment-emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was -20% (range, -98% to +300%). Gene expression analysis in pre- and post-treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV-075 which were consistently modulated in a dose-dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m. Conclusions: Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML. Clinical trial information: NCT02391480.

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Targeting AMPK-ULK1-mediated autophagy for combating BET inhibitor resistance in acute myeloid leukemia stem cells

Autophagy ◽

10.1080/15548627.2016.1278328 ◽

2017 ◽

Vol 13 (4) ◽

pp. 761-762 ◽

Cited By ~ 28

Author(s):

Ji Eun Jang ◽

Ju-In Eom ◽

Hoi-Kyung Jeung ◽

June-Won Cheong ◽

Jung Yeon Lee ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Leukemia Stem Cells ◽

Bet Inhibitor ◽

Inhibitor Resistance ◽

Acute Myeloid

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Loss of Kat2A Enhances Transcriptional Noise and Depletes Acute Myeloid Leukemia Stem-Like Cells

10.1101/446096 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ana Filipa Domingues ◽

Rashmi Kulkarni ◽

George Giotopoulos ◽

Shikha Gupta ◽

Shengjiang Tan ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Gene Promoters ◽

Cancer Evolution ◽

Monocytic Differentiation ◽

Self Renewal ◽

Cell Propagation ◽

Chromatin Profiling ◽

Transcriptional Bursting ◽

Acute Myeloid

ABSTRACTAcute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective myelo-monocytic differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics, we demonstrate that Kat2a contributes to leukemia propagation through homogeneity of transcriptional programs and preservation of leukemia stem-like cells. Kat2a loss reduces transcriptional bursting frequency in a subset of gene promoters, generating enhanced variability of transcript levels but minimal effects on mean gene expression. Destabilization of target programs shifts cellular equilibrium out of self-renewal towards differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and at distinct stages of cancer evolution.

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Electrophoretic and cytochemical characterization of alpha-naphthyl acetate esterases in acute myeloid leukemia: relationships with membrane receptor and monocyte-specific antigen expression

Blood ◽

10.1182/blood.v63.3.579.bloodjournal633579 ◽

1984 ◽

Vol 63 (3) ◽

pp. 579-587

Author(s):

CS Scott ◽

DC Linch ◽

AG Bynoe ◽

C Allen ◽

N Hogg ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Specific Antigen ◽

Diagnostic Category ◽

Membrane Receptors ◽

Monocytic Differentiation ◽

Morphological Criteria ◽

Myeloid Leukemias ◽

Naphthyl Acetate ◽

Acute Myeloid

Alpha-naphthyl acetate esterases (ANAE) were examined by cytochemical and isoelectric focusing (IEF) techniques in 48 cases of acute myeloid leukemia that were classified by conventional morphological criteria. Four main types of ANAE isoenzyme patterns were found by IEF, and comparisons with the expression of membrane receptors (Fc-IgG and C3b) and monocyte-specific antigens (UCHM1, UCHALF, and E11) suggest relationships between ANAE isoenzyme synthesis and distinct myeloid maturational stages. The results further indicate that the blast cells of acute myelomonocytic leukemia (AMML) may represent an immature variant of monocytic leukemia (AMoL) and that morphological examination alone is inadequate in the assessment of monocytic differentiation in acute myeloid leukemias. Inhibition studies of cytochemical ANAE activity with sodium fluoride (NaF) show that the presence of NaF- sensitive or NaF-resistant ANAE enzymes is often unrelated to the diagnostic category of acute leukemia. The results of this study are examined in relation to current concepts of myeloid differentiation, and the application of these findings to the subclassification of acute myeloid leukemias is discussed.

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MEN1112/OBT357, an Anti Bst1/CD157 Humanized Antibody Inducing Acute Myelogenous Leukemia (AML) Blast Depletion in an Autologous Ex Vivo Assay: A Potential New Targeted Therapy for AML

Blood ◽

10.1182/blood.v126.23.788.788 ◽

2015 ◽

Vol 126 (23) ◽

pp. 788-788

Author(s):

Adriano Venditti ◽

Francesco Buccisano ◽

Luca Maurillo ◽

Maria Ilaria Del Principe ◽

Andrea Coppola ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Ex Vivo ◽

Myelogenous Leukemia ◽

Monocytic Differentiation ◽

Healthy Donors ◽

Ex Vivo Assay ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a disease with a poor outcome and novel approaches are needed to improve survival and decrease toxicity of current therapies. Bst1/CD157 is a protein belonging to the ADP-ribosyl-cyclase family expressed on monocytes and neutrophils. This antigen was shown to be also expressed in peripheral blood (PB) and bone marrow (BM) blasts of acute myeloid leukemia (AML) patients either at primary diagnosis or at relapse(1,2,3). MEN1112/OBT357 is a humanized, de-fucosylated antibody targeting Bst1/CD157 with high affinity and developed to generate antibody dependent cell-mediated cytotoxicity (ADCC) response against AML blasts. Peripheral blood (PB) and bone marrow (BM) samples of 38 AML patients (29 at diagnosis, 6 at relapse, 3 resistant), have been analyzed for the expression of Bst1/CD157 on AML blast cells by fluorescence-activated cell sorting (FACS) using a PE conjugated form of MEN1112/OBT357. Bst1/CD157 expression has been confirmed in 91% and 96% of PB and BM AML samples, respectively. Furthermore, statistical analysis demonstrated that monocyte-oriented blasts are characterized by a brighter expression of Bst1/CD157 compared to blasts of non-monocytic lineage. The efficacy of MEN1112/OBT357 in depleting AML blasts was evaluated through FACS analysis in an autologous ex vivo assay performed on whole blood. The assay was set up using blood from healthy donors exposed to 10 μg/ml Rituximab for 18 hours to induce B cell depletion. In the same conditions, the ability of 10 μg/ml MEN1112/OBT357 to induce blasts depletion was tested.In whole PB,MEN1112/OBT357 was able to deplete AML blasts in 15/32 evaluable cases (46%). In BM, MEN1112/OBT357 induced blast depletion in 9/24 evaluable cases (36%). Interestingly, higher depletion rate was observed in relapse/refractory patients. When CD16A-158Phe/Val polymorphisms were analyzed utilizing a sequence based typing (SBT) assay, it was demonstrated that AML blast depletion was independent by FcRg polymorphism. Furthermore, no significant shedding of Bst1/CD157 antigen was observed in sera from AML patients, compared to the sera from patients with other hematologic diseases or healthy donors. In summary, we confirmed the frequent expression of Bst1/CD157 on blasts from AML patients, with the brightest pattern of positivity observed in cases belonging to monocytic differentiation lineage. MEN1112/OBT357 also induced a promising ADCC against AML blasts in an autologous setting, which is independent from FcR g phenotype. Since in vivo the exposure of AML blasts to MEN1112/OBT357 largely exceeds the incubation time of the depletion assay, we expect a further improvement of its anti-leukemic effect in the clinical setting. Based on these results, a phase I study in patients with relapsed or refractory AML has been initiated in December 2014. Disclosures Bellarosa: Menarini Ricerche: Employment. Bressan:Menarini Ricerche: Employment. Wilson:Oxford Biotherapeutics: Employment. Manzini:Menarini Ricerche: Employment. Capriati:Menarini Ricerche SpA: Employment. Simonelli:Menarini Ricerche SpA: Employment. Binaschi:Menarini Ricerche: Employment.

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