Megan A. Hatlen

BLU-808: A Potent and Selective Oral Small Molecule Wild-Type KIT Tyrosine Kinase Inhibitor for Allergic Conditions

Megan A. Hatlen, Andrew M. Haidle, Doug Wilson, Priyanka Sawant et autres

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BLU-808, a Potent and Selective Small Molecule Inhibitor of Wild-type c-KIT for Mast Cell Disorders

Alexandra R. Grassian, Andrew M. Haidle, Sophia AuDuong, James Α. Baker et autres

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Abstract 1279: Development of a selective CDK2-E inhibitor in CCNE driven cancers

Yoon Jong Choi, Steve Wenglowsky, Victoria E. Brown, Neil Bifulco et autres

Abstract Background: Cyclin dependent kinases (CDK) comprise a family of proteins which are activated upon cyclin binding to promote cell cycle progression. Historically, CDK family inhibitors have had limited utility in the clinic due to 1) toxicities associated with broad spectrum CDK …

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Abstract A118: Identification of resistance mechanisms to FGFR4 targeted therapy in hepatocellular carcinoma

Megan A. Hatlen, Oleg Schmidt‐Kittler, Cori-Ann Sherwin, Emily Rozsahegyi et autres

Abstract When on-target resistance mutations occur in response to potent and selective therapeutics, the target is often considered a validated driver of disease. Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide whose drivers remain unvalidated because approved therapies utilize …

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Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma

Megan A. Hatlen, Oleg Schmidt-Kittler, Cori Ann Sherwin, Emily Rozsahegyi et autres

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with no clinically confirmed oncogenic driver. Although preclinical studies implicate the FGF19 receptor FGFR4 in hepatocarcinogenesis, the dependence of human cancer on FGFR4 has not been demonstrated. Fisogatinib (BLU-554) is …

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The Evolution of Selective FGFR4 Inhibitors for FGF19-Driven Malignancies

Joseph L. Kim, Chandra Miduturu, Megan A. Hatlen, Klaus P. Hoeflich et autres

Medicinal Chemistry Reviews is an outstanding 680 page volume providing timely and critical reviews of important topics in medicinal chemistry. It is provided free of charge to MEDI members in electronic format. Members can also order a print copy, for the cost …

Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms

Takashi Asai, Megan A. Hatlen, Chen Lossos, Delphine Ndiaye‐Lobry et autres

Multiple myeloma is a plasma cell neoplasm with an extremely variable clinical course. Animal models are needed to better understand its pathophysiology and for preclinical testing of potential therapeutic agents. Hematopoietic cells expressing the hypermorphic Rad50(s) allele show hematopoietic failure, which can …

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Differential role of Id1 in MLL-AF9–driven leukemia based on cell of origin

Na Man, Xiao‐Jian Sun, Yurong Tan, Marta García‐Cao et autres

Inhibitor of DNA binding 1 (Id1) functions as an E protein inhibitor, and overexpression of Id1 is seen in acute myeloid leukemia (AML) patients. To define the effects of Id1 on leukemogenesis, we expressed MLL-AF9 in fetal liver (FL) cells or bone …

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Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles

Megan A. Hatlen, Kanika S. Arora, Vladimir Vacic, Ewa A. Grabowska et autres

t(8;21) is one of the most frequent chromosomal abnormalities observed in acute myeloid leukemia (AML). However, expression of AML1-ETO is not sufficient to induce transformation in vivo. Consistent with this observation, patients with this translocation harbor additional genetic abnormalities, suggesting a requirement …

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Integrative Analysis of the Mutational Landscape of Mouse and Human AML Identifies Functionally Relevant Leukemia Disease Alleles

Megan A. Hatlen, Kanika S. Arora, Vladimir Vacic, Ewa A. Grabowska et autres

Abstract t(8;21) is the most frequent chromosomal abnormality in acute myeloid leukemia (AML), occurring in 4-12% of adult and 12-30% of pediatric patients. This translocation fuses the N-terminus of AML1 to nearly the entire coding region of ETO, resulting in expression of …

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Prmt5 Negatively Regulates Erythropoiesis By Multiple Mechanisms, Including Controlling DNA Methyltransferase 3A Protein Levels

Pierre-Jacques Hamard, Luisa Luciani, Fan Liu, Guoyan Cheng et autres

Abstract The shift in sites of hematopoiesis during embryonic development leads to primitive hematopoiesis within the fetal liver at E12.5, which generates primarily erythrocytes. Definitive hematopoiesis, which occurs within the bone marrow, follows at birth. During the erythroid differentiation of fetal hematopoiesis, …

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Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression

Lan Wang, Na Man, Xiao‐Jian Sun, Yurong Tan et autres

Transcriptional regulators are recurrently altered through translocations, deletions, or aberrant expression in acute myeloid leukemia (AML). Although critically important in leukemogenesis, the underlying pathogenetic mechanisms they trigger remain largely unknown. Here, we identified that Id1 (inhibitor of DNA binding 1) plays a …

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