Acute myeloid leukemia (AML) is the most common type of leukemia in adults with approximately 20,000 new cases and 10,000 deaths each year in the United States. Despite considerable improvement of survival rates for patients with leukemia over the past 50 years, the overall five-year relative survival rate for AML patients is only approximately 20 percent.
Leukemia stem cells (LSCs) are now recognized as the critical “seeds” of leukemia, and represent a fundamental challenge thought to underlie poor outcome due to their relative resistance to standard chemotherapy. Our long-term goal is to elucidate the molecular mechanism(s) regulating the maintenance of LSCs, to understand how they differ from normal hematopoietic stem cells, and to develop novel LSC-targeted therapeutics. Using a genetic mouse model of a common chromosome aberration found in AML patients, known as inv(16), we have shown that leukemia arises as a result of a multi-step transformation process involving mutations that disrupt hematopoietic differentiation, and those that deregulate proliferation and self-renewal programs.
Our current research efforts are directed towards understanding the molecular pathways and functional mediators regulating normal hematopoiesis as well as those underlying leukemogenesis using a combination of genetics, genomics, biochemistry, proteomics, molecular biology and cellular biology approaches. We use defined genetic mouse models as an experimental system to identify molecular pathways and targets, and primary cells from AML patients to validate the findings and perform further translational and preclinical studies. We believe that a comprehensive understanding of oncogenic mechanisms will enable rational design and selection of improved cancer treatments.
Chen MJ, Kuo YH, Tian XC and Chen TT. (2002) Novel biological activities of fish pro-IGF-I E-peptides: studies on effects of fish pro-IGF-I E-peptides on morphological change, anchorage-independent cell division, and invasiveness in tumor cells. Gen. Comp. Endocrinol 126(3): 342-351. PMID: 12093122
Kuo YH and Chen TT. (2002) Novel biological activities of pro-IGF-I E-peptides: regulation of morphological differentiation and anchorage-independent growth in neuroblastoma cells. Exp. Cell Res. 280(1): 75-89. PMID: 12372341
Kuo YH and Chen, TT. (2003) Specific binding of pro-IGF-I E-peptides to putative cell surface receptors on human neuroblastoma cells. Gen. Comp. Endocrinol. 132(2): 231-240. PMID: 12812770
Landrette SF, Kuo YH, Hensen K, Barjesteh van Waalwijk van Doorn-Khosrovani S, Perrat PN, Van de Ven WJ, Delwel R, Castilla LH. (2005) Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. Blood 105(7): 2900-7. PMID: 15585652
Kuo YH, Landrette SF, Heilman SA, Perrat PN, Garrett L, Liu PP, Le Beau MM, Kogan SC, Castilla LH. (2006) Cbf(beta)-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell 9(1): 57-68. PMID: 16413472 (Cover).
Heilman SA, Kuo YH, Valk PJM, Castilla LH. (2006) Cbf(beta) reduces Cbf(beta)-SMMHC-associated acute myeloid leukemia in mice. Cancer Research 66(23): 11214-8. PMID: 17145866
Kuo YH, Gerstein RM, and Castilla LH. (2008) Cbf(beta)-SMMHC impairs differentiation of common lymphoid progenitors and reveals an essential role for RUNX in early B cell development. Blood 111(3): 1543-51. PMID: 17940206; PMCID: PMC2214760
Kuo YH, Zaidi SK, Gornostaeva S, Komori T, Stein GS, Castilla LH. (2009) Runx2 induces acute myeloid leukemia in cooperation with Cbf(beta)-SMMHC in mice. Blood 113(14): 3323-32. PMID: 19179305; PMCID: PMC2665897
Pulikkan JA, Madera D, Xue L, Bradley P, Landrette SF, Kuo YH, Abbas S, Zhu LJ, Valk P, Castilla LH. (2012) THPO/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling. Blood 120(4): 868-79. PMID: 22613795; PMCID: PMC3412349
Jeannet R, Cai, Q, Liu H, Vu H, Kuo YH. (2013) Alcam regulates long-term hematopoietic stem cell engraftment and self-renewal. Stem Cells 31(3): 560-71. PMID: 23280653; PMCID: PMC3832064
Dos Santos C. McDonald T, Ho YW, Liu H, Lin A, Forman SJ, Kuo YH*, and Bhatia R*. (2013) The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cell by chemotherapeutic agents. Blood 122(11): 1900-13. PMID: 23896410. (* Equal contribution, co-correspondence)
Hossain DM, Dos Santos C, Zhang Q, Kozlowska A, Liu H, Gao C, Moreira D, Swiderski P, Jozwiak A, Kline J, Forman S, Bhatia R, Kuo YH*, and Kortylewski M*. (2014) Leukemia cell-targeted STAT3 silencing and TLR-9-triggering generate systemic antitumor immunity. Blood 123(1): 15-25. PMID: 24169824; PMCID: PMC3879904 (* Equal contribution, co-correspondence)
Kortylewski M and Kuo YH. (2014) Push and release: TLR9 activation plus STAT3 blockade for systemic antitumor immunity. OncoImmunology 3(1): e27441. PMID: 24800162; PMCID: PMC4006856
Li L, Osdal T, Ho Y, Chun S, McDonald T, Agarwal P, Lin A, Chu S, Qi J, Li L, Hsieh Y-T, Dos Santos C, Yuan H, Popa M, Gjertsen BT, Kuo YH, Chen W, Lain S, McCormack E and Bhatia R. (2014) SIRT1 activation by a c-MYC Oncogenic Network Promotes the Maintenance and Drug Resistance of Human FLT3-ITD Acute Myeloid Leukemia Stem Cells. Cell Stem Cell 15(4): 431-46. PMID: 25280219; PMCID: PMC4305398
Kuo YH* and Bhatia R*. (2014). Pushing the Limits: Defeating Leukemia Stem Cells by Depleting Telomerase. Cell Stem Cell 15, 673-675. PMID: 25479742;PMCID: PMC4394378. (*Correspondence)
Qi J, Singh S, Hua W-K, Cai Q, Chao S-W, Li L, Liu H, Ho Y, McDonald T, Lin A, Marcucci G, Bhatia R, Huang W-J, Chang C-I, Kuo YH. (2015) HDAC8 inhibition specifically targets inv(16) acute myeloid leukemia stem cells by restoring p53 acetylation. Cell Stem Cell, http://dx.doi.org/10.1016/j.stem.2015.08.004