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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 Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha.
Academic Article Differences in oncogenic potency but not target cell specificity distinguish the two forms of the BCR/ABL oncogene.
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 p16Ink4a or p19Arf loss contributes to Tal1-induced leukemogenesis in mice.
Academic Article The Notch1/c-Myc pathway in T cell leukemia.
Academic Article Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL.
Academic Article The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice.
Academic Article A DNA-binding mutant of TAL1 cooperates with LMO2 to cause T cell leukemia in mice.
Academic Article Core transcriptional regulatory circuit controlled by the TAL1 complex in human T cell acute lymphoblastic leukemia.
Academic Article TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia.
Academic Article The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia.
Academic Article NF-kappaB activation in premalignant mouse tal-1/scl thymocytes and tumors.
Academic Article Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner.
Academic Article Activating Notch1 mutations in mouse models of T-ALL.
Academic Article NFKB1 is a direct target of the TAL1 oncoprotein in human T leukemia cells.
Academic Article Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc.
Academic Article Targeting the Notch1 and mTOR pathways in a mouse T-ALL model.
Academic Article The TLX1 oncogene drives aneuploidy in T cell transformation.
Academic Article Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL.
Academic Article ABL oncogenes directly stimulate two distinct target cells in bone marrow from 5-fluorouracil-treated mice.
Concept Oncogene Proteins, Fusion
Concept Proto-Oncogene Proteins c-rel
Concept Oncogenes
Concept Oncogene Proteins
Concept Proto-Oncogene Proteins c-bcl-2
Concept Proto-Oncogene Proteins c-mdm2
Concept Proto-Oncogene Proteins c-myb
Concept Proto-Oncogene Proteins c-akt
Concept Proto-Oncogene Proteins c-myc
Concept Proto-Oncogene Proteins
Academic Article c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells.
Academic Article Leukemia propagating cells Akt up.
Academic Article Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.
Academic Article Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199.
Academic Article RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.
Academic Article NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-?B-Dependent and -Independent Functions.
Academic Article The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.
Academic Article Mdm2 Phosphorylation Regulates Its Stability and Has Contrasting Effects on Oncogene and Radiation-Induced Tumorigenesis.

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