Browsing by Author "Haneline, Laura"

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    The epigenetic regulator CXXC finger protein 1 is essential for murine hematopoiesis
    (PLoS, 2014-12-03) Chun, Kristin T.; Li, Binghui; Dobrota, Erika; Tate, Courtney; Lee, Jeong-Heon; Khan, Shehnaz; Haneline, Laura; HogenEsch, Harm; Skalnik, David G.; Department of Pediatrics, IU School of Medicine
    CXXC finger protein 1 (Cfp1), encoded by the Cxxc1 gene, binds to DNA sequences containing an unmethylated CpG dinucleotide and is an epigenetic regulator of both cytosine and histone methylation. Cxxc1-null mouse embryos fail to gastrulate, and Cxxc1-null embryonic stem cells are viable but cannot differentiate, suggesting that Cfp1 is required for chromatin remodeling associated with stem cell differentiation and embryogenesis. Mice homozygous for a conditional Cxxc1 deletion allele and carrying the inducible Mx1-Cre transgene were generated to assess Cfp1 function in adult animals. Induction of Cre expression in adult animals led to Cfp1 depletion in hematopoietic cells, a failure of hematopoiesis with a nearly complete loss of lineage-committed progenitors and mature cells, elevated levels of apoptosis, and death within two weeks. A similar pathology resulted following transplantation of conditional Cxxc1 bone marrow cells into wild type recipients, demonstrating this phenotype is intrinsic to Cfp1 function within bone marrow cells. Remarkably, the Lin- Sca-1+ c-Kit+ population of cells in the bone marrow, which is enriched for hematopoietic stem cells and multi-potential progenitor cells, persists and expands in the absence of Cfp1 during this time frame. Thus, Cfp1 is necessary for hematopoietic stem and multi-potential progenitor cell function and for the developmental potential of differentiating hematopoietic cells.
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    Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by proinflammatory cytokine–induced lncRNA Morrbid
    (American Society for Clinical Investigation, 2021-01-04) Cai, Zhigang; Lu, Xiaoyu; Zhang, Chi; Nelanuthala, Sai; Aguilera, Fabiola; Hadley, Abigail; Ramdas, Baskar; Fang, Fang; Nephew, Kenneth; Kotzin, Jonathan J.; Williams, Adam; Henao-Mejia, Jorge; Haneline, Laura; Kapur, Reuben; Microbiology and Immunology, School of Medicine
    Diabetes mellitus (DM) is a risk factor for cancer. The role of DM-induced hyperglycemic (HG) stress in blood cancer is poorly understood. Epidemiologic studies show that individuals with DM are more likely to have a higher rate of mutations in genes found in pre-leukemic hematopoietic stem and progenitor cells (pre-LHSPCs) including TET2. TET2-mutant pre-LHSPCs require additional hits to evolve into full-blown leukemia and/or an aggressive myeloproliferative neoplasm (MPN). Intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the extrinsic factors are poorly understood. Using a mouse model carrying Tet2 haploinsufficiency to mimic the human pre-LHSPC condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces hyperglycemia and type 1 DM, we show that the compound mutant mice developed a lethal form of MPN and/or acute myeloid leukemia (AML). RNA-Seq revealed that this was due in part to upregulation of proinflammatory pathways, thereby generating a feed-forward loop, including expression of the antiapoptotic, long noncoding RNA (lncRNA) Morrbid. Loss of Morrbid in the compound mutants rescued the lethality and mitigated MPN/AML. We describe a mouse model for age-dependent MPN/AML and suggest that hyperglycemia acts as an environmental driver for myeloid neoplasms, which could be prevented by reducing expression levels of the inflammation-related lncRNA Morrbid.
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    Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells
    (Elsevier, 2022) Ramdas, Baskar; Yuen, Lisa Deng; Palam, Lakshmi Reddy; Patel, Roshini; Pasupuleti, Santhosh Kumar; Jideonwo, Victoria; Zhang, Ji; Maguire, Callista; Wong, Eric; Kanumuri, Rahul; Zhang, Chujing; Sandusky, George; Chan, Rebecca J.; Zhang, Chi; Stieglitz, Elliot; Haneline, Laura; Kapur, Reuben; Pediatrics, School of Medicine
    Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton’s tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment.