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Michelle Kelliher received her B.A. in Biology from Smith College and a M.S. degree in Biology from Yale University. She received her Ph.D. in Immunology from Tufts University Sackler School of Biomedical Sciences and completed her post-doctoral training in the Department of Genetics at Harvard Medical School. In 1998, Dr. Kelliher joined the UMMS Faculty and is currently a Professor in the Molecular, Cellular and Cancer Biology Department. Dr. Kelliher is a Scholar and Stohlman Scholar of the Leukemia and Lymphoma Society of America and a Sidney Kimmel Cancer Scholar.  Her research is supported by the NIH (NCI and NIAID), a Hyundai Hope Grant for Pediatric Cancers and an Alex’s Lemonade Stand Innovator Award.

Visit the Kelliher Lab website: http://labs.umassmed.edu/kelliherlab/

Mechanisms of Leukemogenesis

Genetically engineered mouse model (GEMM) of pediatric T-ALL

T cell acute lymphoblastic leukemia (T-ALL) is largely caused by the activation of TAL1, LMO1/2 and the NOTCH1 oncogenes. To model the disease in mice, we ectopically expressed the basic-helix-loop-helix (bHLH) transcription factor TAL1 and its binding partner LMO2 in developing mouse thymocytes. These transgenic mice develop T-ALL that resembles the human disease. We have shown that the DNA binding activity of TAL1 is not required to induce leukemia in mice and demonstrated that E2A or HEB heterozygosity accelerates TAL1-mediated disease (O’Neil et al., 2001; 2004).  These studies revealed that TAL1 transforms in part, by interfering with the E47/HEB bHLH heterodimer required for the expression of T cell differentiation genes (Figure?). In collaboration with the Look lab, we performed ChIP-seq analyses that demonstrated that TAL1 also participates in a TAL1-GATA3-RUNX1 autoregulatory loop that induces the expression of stem cell genes such as MYB in leukemia (Sanda et al., 2012).

Identifying cooperating oncogenes

We have used our GEMM and retroviral insertional mutagenesis (RIM) to identify genes that cooperate with TAL1 to cause leukemia in mice. The RIM screens revealed recurrent retroviral insertions in the Notch1, Myc and Ikaros loci (Sharma et al., 2006). Consistent with these data, NOTCH1 mutations were discovered in 54% of T-ALL patients and shown to develop spontaneously in our TAL1 transgenic mice (O’Neil et al., 2006). These mouse T-ALLs also express dominant-negative forms of Ikaros, indicating that Ikaros acts as a tumor suppressor in the disease. We then discovered that NOTCH1 contributes to leukemogenesis by directly regulating the expression of MYC (Sharma et al., 2006).

NOTCH1-MYC axis mediates L-IC activity

Leukemia-initiating cells (L-IC) are hypothesized to exhibit extensive proliferative and self-renewal capabilities and thereby mediate relapse. Using our GEMM of T-ALL, we identified the DN3 progenitor population as enriched in L-IC activity. Since NOTCH1 is important in thymic progenitor expansion, we hypothesized that the L-IC may depend on the NOTCH1-MYC pathway for their activity.  We found that treatment with a gamma-secretase inhibitor (GSI) which prevents NOTCH1 activation or the bromodomain 4 (BRD4) inhibitor JQ1, which targets MYC, significantly reduces or eliminates the L-IC population and prevents disease initiation (Tatarek et al., 2011; Roderick et al., 2014). These studies suggested that NOTCH and BRD4 inhibition may target the L-IC and prevent relapse.

Establishing patient-derived xenografts from relapsed pediatric T-ALL and ETP-ALL patients

To translate our findings to the human disease, we generated patient-derived xenografts (PDX) from pediatric T-ALL patients at the time of diagnosis and upon induction failure or relapse. We are using these models to study disease heterogeneity and to test the efficacy of combination targeted therapies. We found that GSI-JQ1 combination therapy was effective in vivo, significantly prolonging survival in PDX models of relapsed pediatric T-ALL (Knoechel et al., 2014).

We are one of a few labs world wide that have also successfully generated PDX models from patients with early thymic progenitor (ETP)-ALL, a particularly treatment resistant ALL subtype. In collaboration with the Letai laboratory, we demonstrated that ETP-ALL is uniquely BCL2-dependent and highly sensitive to treatment in vivo with the BCL2 inhibitor ABT-199 (Chongaile et al., 2014). Our current goals are to examine human L-IC activity in these models and to optimize lentiviral-mediated transduction and CRISPR/Cas9 screening in primary human leukemic cells.

 

RIP Kinases in Cell Death and Inflammation

My laboratory has had a long-standing interest in RIP Kinases and their role in TNF- and TRIF-dependent signaling.  We demonstrated that a RIPK1 deficiency in the mouse results in neonatal lethality due to extensive TNF-induced cell death and inflammation (Kelliher et al., 1998; Cusson et al 2002). We showed that RIPK1 is recruited to the TNF receptor 1 (Tnfr1) and the Toll-like receptors (TLR) 3 and 4 via the adapter TRIF and is stably ubiquitin-modified with K63-linked polyubiquitin chains (Meylan et al., 2004; Lee et al., 2004). We have since established that in addition to TNF-induced apoptosis, RIPK1 regulates a form of programmed necrosis called necroptosis. Necroptosis is thought to require the kinase activities of RIPK1, RIPK3 and MLKL (Figure?) and induces an inflammatory form of cell death. We provide genetic evidence that in the absence of RIPK1, tissues undergo apoptosis and RIPK3-mediated necroptosis. Unlike Ripk1-/- or Ripk1-/-Tnfr1-/- mice, which die during the postnatal period, Ripk1/Tnfr1/Ripk3 triple knock out mice survive to adulthood (Dillon et al., 2014). These in vivo studies demonstrate that RIPK1 is a master regulator of cell death and inflammation.

 

To identify the cell types and tissues that depend on RIPK1 for survival, we developed Ripk1 conditional mice and RIPK1 kinase inactive (D138N) mice.  These mouse models allow us to examine the role of RIPK1 in tissue homeostasis and inflammation. Our published work demonstrates critical survival roles for RIPK1 in the intestinal epithelium, keratinocytes and cells of the hematopoietic lineage (Dannappel, et al., 2014;Roderick et al., 2014). We also demonstrated that RIPK1D138N mice are completely protected from TNF-induced hypothermia and shock in vivo (Polykratis et al., 2014).  These studies indicate that RIP kinase-dependent necroptotic death mediates shock and may contribute to sepsis, raising the possibility that RIPK inhibitors may have clinical utility in these patients and in chronic inflammatory disease.

One or more keywords matched the following items that are connected to Kelliher, Michelle
Item TypeName
Academic Article The death domain kinase RIP mediates the TNF-induced NF-kappaB signal.
Academic Article The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation.
Academic Article The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase.
Academic Article The kinase activity of Rip1 is not required for tumor necrosis factor-alpha-induced IkappaB kinase or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf2.
Academic Article TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB.
Academic Article RIP links TLR4 to Akt and is essential for cell survival in response to LPS stimulation.
Academic Article Interferon regulatory factor 7 is activated by a viral oncoprotein through RIP-dependent ubiquitination.
Academic Article Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains.
Academic Article RIP1 links inflammatory and growth factor signaling pathways by regulating expression of the EGFR.
Academic Article The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice.
Academic Article NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis.
Academic Article A DNA-binding mutant of TAL1 cooperates with LMO2 to cause T cell leukemia in mice.
Academic Article Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production.
Academic Article The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death.
Academic Article TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia.
Academic Article NF-kappaB activation in premalignant mouse tal-1/scl thymocytes and tumors.
Academic Article The death domain kinase RIP1 is essential for tumor necrosis factor alpha signaling to p38 mitogen-activated protein kinase.
Academic Article Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner.
Academic Article Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation.
Academic Article NFKB1 is a direct target of the TAL1 oncoprotein in human T leukemia cells.
Academic Article NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2.
Academic Article Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1.
Concept Transcription Factor TFIIIA
Concept TNF Receptor-Associated Factor 6
Concept Transcription Factor CHOP
Concept Transcription Factor RelB
Concept TNF Receptor-Associated Factor 2
Concept Myeloid Differentiation Factor 88
Concept Interferon Regulatory Factor-7
Concept Receptors, Tumor Necrosis Factor, Type II
Concept Tumor Necrosis Factor-alpha
Concept Ikaros Transcription Factor
Concept Interferon Regulatory Factor-3
Concept Core Binding Factor Alpha 2 Subunit
Concept Core Binding Factor beta Subunit
Concept Receptors, Tumor Necrosis Factor, Type I
Concept Sp1 Transcription Factor
Concept STAT1 Transcription Factor
Concept Receptors, Tumor Necrosis Factor
Concept Eukaryotic Initiation Factor-4A
Concept Transcription Factor RelA
Academic Article RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3.
Academic Article Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo.
Academic Article RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.
Academic Article RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis.
Academic Article Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis.
Academic Article NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-?B-Dependent and -Independent Functions.
Academic Article CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN.
Academic Article RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS.
Academic Article RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia.
Academic Article RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome.
Academic Article Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity.
Academic Article UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response.
Academic Article Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death.
Academic Article Analyzing Necroptosis Using an RIPK1 Kinase Inactive Mouse Model of TNF Shock.
Academic Article RIPK1 Mediates TNF-Induced Intestinal Crypt Apoptosis During Chronic NF-?B Activation.
Academic Article Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation.
Academic Article T cell-derived tumor necrosis factor induces cytotoxicity by activating RIPK1-dependent target cell death.
Concept Tumor Necrosis Factor alpha-Induced Protein 3
Concept Transcription Factor 7-Like 1 Protein
Concept Transcription Factor 3
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