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The Kumar Lab is studying the biology of blood cancers found in children. Our current focus is on two diseases – infant leukemia and Langerhans Cell Histiocytosis (LCH). Leukemia is the most frequent form of childhood cancer. Infants with leukemia face an exceptionally grim prognosis because the pathogenesis of the disease is different than that of leukemia in older children. The majority of leukemias found in infants involve translocations of the MLL gene on chromosome 11q23.
Our lab is studying experimental models of MLL-rearranged leukemia to discover biological pathways that are dysregulated in the leukemic cells. Using knock-in MLL-AF9 mice, we have identified several genes that are abnormally upregulated in hematopoietic cells compared to corresponding wild type cells. These genes and pathways are also up-regulated in leukemia cells of human patients. We are now studying the role of these activated genes in the pathogenesis of leukemia.
Another rare disease most commonly found in children is LCH. Our knowledge and understanding of the pathophysiology of LCH has been limited, hampering the development of specific and effective treatments. In the tumor cells of children with LCH, we identified mutations in the gene MAP2K1, which encodes for the serine/threonine kinase MEK. We are currently investigating the role of these mutations in the pathogenesis of LCH.
Karkare S, Chhipa RR, Anderson J, Liu X, Henry H, Gasilina A, Nassar N, Roychoudhury J, Clark JP, Kumar A, Pauletti GM, Ghosh PK, Dasgupta B. Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell-cycle arrest and suppresses glioblastoma growth. Clin Cancer Res. 2014 Jan 1;20(1):199-212.
Khandelwal P, Lawrence J, Filipovich AH, Davies SM, Bleesing JJ, Jordan MB, Mehta P, Jodele S, Grimley MS, Kumar A, Myers K, Marsh RA. The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versus-host disease in pediatric patients. Pediatr Transplant. 2014 Feb;18(1):94-102.
Xiaona Liu, Rishi Raj Chhipa, Shabnam Pooya, Matthew Wortman, Sara Yachyshin, Lionel M. L. Chow, Ashish Kumar, Xuan Zhou, Ying Sun, Brian Quinn, Christopher McPherson, Ronald E. Warnick, Ady Kendler, Shailendra Giri, Jeroen Poels, Koenraad Norga, Benoit Viollet, Gregory A. Grabowski, Biplab Dasgupta. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):E435-44.
Jing Zhou, Jun Wu, Bo Li1, Dan Liu, Jian Yu, Xiaomei Yan, Si Zheng, Jiguang Wang, Lixia Zhang, Lin Zhang, Fuhong He, Qiang Li, Aili Chen, Yue Zhang, Xinghui Zhao, Yinghui Guan, Xiaohong Zhao1, Jin Yan, Jun Ni, Marcelo A. Nobrega, Bob Löwenberg, R Delwel, Peter J.M. Valk, Ashish Kumar, Lu Xie, Daniel G. Tenen, Gang Huang and Qian-fei Wang. PU.1 is Essential for MLL Leukemia Partially via Crosstalk with the MEIS/HOX Pathway. Leukemia. 2014 Jul;28(7):1436-48.
Jing H, Zhang Q, Zhang Y, Hill BJ, Dove CG, Gelfand EW, Atkinson TP, Uzel G, Matthews HF, Mustillo PJ, Lewis DB, Kavadas FD, Hanson IC, Kumar AR, Geha RS, Douek DC, Holland SM, Freeman AF, Su HC. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. J Allergy Clin Immunol. 2014 Jun;133(6):1667-75.
Marsh RA, Rao K, Satwani P, Lehmberg K, Müller I, Li D, Kim MO, Fischer A, Latour S, Sedlacek P, Barlogis V, Hamamoto K, Kanegane H, Milanovich S, Margolis DA, Dimmock D, Casper JT, Douglas DN, Amrolia PJ, Veys P, Kumar AR, Jordan BM, Bleesing J, Filipovich A. Allogeneic Hematopoietic Cell Transplantation for XIAP Deficiency: An International Survey Reveals Poor Outcomes. Blood. 2013 Feb 7;121(6):877-83.
Marsh RA, Kim MO, Liu C, Bellman D, Hart L, Grimley M, Kumar A, Jodele S, Myers KC, Chandra S, Leemhuis T, Mehta PA, Bleesing JJ, Davies SM, Jordan MB, Filipovich AH. An intermediate alemtuzumab schedule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis. Biol Blood Marrow Transplant. 2013 Nov;19(11):1625-31.
Unnisa Z, Clark JP, Roychoudhury J, Thomas E, Tessarollo L, Copeland NG, Jenkins NA, Grimes HL, Kumar AR.Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress. Blood. 2012.
Bindels EM, Havermans M, Lugthart S, Erpelinck C, Wocjtowicz E, Krivtsov AV, Rombouts E, Armstrong SA, Taskesen E, Haanstra JR, Beverloo HB, Döhner H, Hudson WA, Kersey JH, Delwel R, Kumar AR.EVI1 is critical for the pathogenesis of a subset of MLL-AF9 rearranged AMLs.Blood. Jun 14;119(24):5838-49. 2012.
Kumar AR, Yao Q, Li Q, Sam TN and Kersey JH. t(4;11) leukemias display addiction to MLL-AF4 but not to AF4-MLL. Leukemia Research. 35(3):305-9. 2010.
Kumar AR, Sarver A, Wu B and Kersey JH. Meis1 maintains ‘stemness’ signature in MLL-AF9 leukemia. Blood. Apr 29;115(17):3642-3. 2010.
Kumar AR, Li Q, Hudson WA, Chen W, Yao Q, Sam TN, Wu B, Lund EA, Kowal BJ and Kersey JH. A role for MEIS1 in MLL-fusion gene leukemia. Blood. Feb 19;113(8):1756-8. 2009.
Chen W, Kumar AR, Hudson WA, Li Q, Wu B, Staggs RA, Lund EA, Sam TN and Kersey JH. Malignant transformation initiated by Mll-AF9: Gene dosage and critical target cells. Cancer Cell. May; 13: 432-440. 2008.
Ashish Kumar, MD, PhDDivision of Bone Marrow Transplantation and Immune DeficiencyCancer and Blood Diseases Institute
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