Skip to main content
SpringerLink
Log in

Molecular Basis and Targeted Inhibition of CBFβ-SMMHC Acute Myeloid Leukemia

  • Chapter
  • First Online:
RUNX Proteins in Development and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 962))

Abstract

Acute myeloid leukemia (AML) is characterized by recurrent chromosomal rearrangements that encode for fusion proteins which drive leukemia initiation and maintenance. The inv(16) (p13q22) rearrangement is a founding mutation and the associated CBFβ-SMMHC fusion protein is essential for the survival of inv(16) AML cells. This Chapter will discuss our understanding of the function of this fusion protein in disrupting hematopoietic homeostasis and creating pre-leukemic blasts, in its cooperation with other co-occurring mutations during leukemia initiation, and in leukemia maintenance. In addition, this chapter will discuss the current approaches used for the treatment of inv(16) AML and the recent development of AI-10-49, a selective targeted inhibitor of CBFβ-SMMHC/RUNX1 binding, the first candidate targeted therapy for inv(16) AML.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Bakshi, R., Hassan, M. Q., Pratap, J., Lian, J. B., Montecino, M. A., Van Wijnen, A. J., et al. (2010). The human SWI/SNF complex associates with RUNX1 to control transcription of hematopoietic target genes. Journal of Cellular Physiology, 225, 569–576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ben-Ami, O., Friedman, D., Leshkowitz, D., Goldenberg, D., Orlovsky, K., Pencovich, N., et al. (2013). Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1. Cell Reports, 4, 1131–1143.

    Google Scholar 

  • Bennett, J. M., Catovsky, D., Daniel, M. T., Flandrin, G., Galton, D. A., Gralnick, H. R., & Sultan, C. (1976). Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. British Journal of Haematology, 33, 451–458.

    Article  CAS  PubMed  Google Scholar 

  • Blyth, K., Cameron, E. R., & Neil, J. C. (2005). The RUNX genes: Gain or loss of function in cancer. Nature Reviews Cancer, 5, 376–387.

    Article  CAS  PubMed  Google Scholar 

  • Boissel, N., Leroy, H., Brethon, B., Philippe, N., De Botton, S., Auvrignon, A., et al. (2006). Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia, 20, 965–970.

    Article  CAS  PubMed  Google Scholar 

  • Britos-Bray, M., Ramirez, M., Cao, W., Wang, X., Liu, P. P., Civin, C. I., & Friedman, A. D. (1998). CBFbeta-SMMHC, expressed in M4eo acute myeloid leukemia, reduces p53 induction and slows apoptosis in hematopoietic cells exposed to DNA-damaging agents. Blood, 92, 4344–4352.

    CAS  PubMed  Google Scholar 

  • Cao, W., Britos-Bray, M., Claxton, D. F., Kelley, C. A., Speck, N. A., Liu, P. P., & Friedman, A. D. (1997). CBF beta-SMMHC, expressed in M4Eo AML, reduced CBF DNA-binding and inhibited the G1 to S cell cycle transition at the restriction point in myeloid and lymphoid cells. Oncogene, 15, 1315–1327.

    Article  CAS  PubMed  Google Scholar 

  • Care, R. S., Valk, P. J., Goodeve, A. C., Abu-Duhier, F. M., Geertsma-Kleinekoort, W. M., wilson, G. A., et al. (2003). Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. British Journal of Haematology, 121, 775–777.

    Article  CAS  PubMed  Google Scholar 

  • Castilla, L. H., Wijmenga, C., Wang, Q., Stacy, T., Speck, N. A., Eckhaus, M., et al. (1996). Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell, 87, 687–696.

    Article  CAS  PubMed  Google Scholar 

  • Castilla, L. H., Garrett, L., Adya, N., Orlic, D., Dutra, A., Anderson, S., et al. (1999). The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nature Genetics, 23, 144–146.

    Article  CAS  PubMed  Google Scholar 

  • Castilla, L. H., Perrat, P., Martinez, N. J., Landrette, S. F., Keys, R., Oikemus, S., et al. (2004). Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America, 101, 4924–4929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng, C. K., Li, L., Cheng, S. H., Lau, K. M., Chan, N. P., Wong, R. S., et al. (2008). Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia. Blood, 112, 3391–3402.

    Google Scholar 

  • Chin, D. W., Watanabe-Okochi, N., Wang, C. Q., Tergaonkar, V., & Osato, M. (2015). Mouse models for core binding factor leukemia. Leukemia, 29, 1970–1980.

    Article  CAS  PubMed  Google Scholar 

  • Claxton, D. F., Liu, P., Hsu, H. B., Marlton, P., Hester, J., Collins, F., et al. (1994). Detection of fusion transcripts generated by the inversion 16 chromosome in acute myelogenous leukemia. Blood, 83, 1750–1756.

    CAS  PubMed  Google Scholar 

  • Corces-Zimmerman, M. R., Hong, W. J., Weissman, I. L., Medeiros, B. C., & Majeti, R. (2014). Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proceedings of the National Academy of Sciences of the United States of America, 111, 2548–2553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cunningham, L., Finckbeiner, S., Hyde, R. K., Southall, N., Marugan, J., Yedavalli, V. R., et al. (2012). Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBFbeta interaction. Proceedings of the National Academy of Sciences of the United States of America, 109, 14592–14597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • D’costa, J., Chaudhuri, S., Civin, C. I., & Friedman, A. D. (2005). CBFbeta-SMMHC slows proliferation of primary murine and human myeloid progenitors. Leukemia, 19, 921–929.

    Article  PubMed  Google Scholar 

  • Delaunay, J., Vey, N., Leblanc, T., Fenaux, P., Rigal-Huguet, F., Witz, F., et al. (2003). Prognosis of inv(16) /t(16;16) acute myeloid leukemia (AML): A survey of 110 cases from the French AML Intergroup. Blood, 102, 462–469.

    Google Scholar 

  • Ding, L., Ley, T. J., Larson, D. E., Miller, C. A., Koboldt, D. C., Welch, J. S., et al. (2012). Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature, 481, 506–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duployez, N., Marceau-Renaut, A., Boissel, N., Petit, A., Bucci, M., Geffroy, S., et al. (2016). Comprehensive mutational profiling of core binding factor acute myeloid leukemia. Blood, 127, 2451–2459.

    Article  CAS  PubMed  Google Scholar 

  • Egawa, T., Tillman, R. E., Naoe, Y., Taniuchi, I., & Littman, D. R. (2007). The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells. The Journal of Experimental Medicine, 204, 1945–1957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Enright, H., Weisdorf, D., Peterson, L., Rydell, R. E., Kaplan, M. E., & Arthur, D. C. (1992). Inversion of chromosome 16 and dysplastic eosinophils in accelerated phase of chronic myeloid leukemia. Leukemia, 6, 381–384.

    CAS  PubMed  Google Scholar 

  • Farag, S. S., Archer, K. J., Mrozek, K., Ruppert, A. S., Carroll, A. J., Vardiman, J. W., et al. (2006). Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: Results from Cancer and Leukemia Group B 8461. Blood, 108, 63–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fotouhi, N., & Graves, B. (2005). Small molecule inhibitors of p53/MDM2 interaction. Current Topics in Medicinal Chemistry, 5, 159–165.

    Article  CAS  PubMed  Google Scholar 

  • Goemans, B. F., Zwaan, C. M., Miller, M., Zimmermann, M., Harlow, A., Meshinchi, S., et al. (2005). Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia, 19, 1536–1542.

    Article  CAS  PubMed  Google Scholar 

  • Goyama, S., Schibler, J., Cunningham, L., Zhang, Y., Rao, Y., Nishimoto, N., et al. (2013). Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. The Journal of Clinical Investigation, 123, 3876–3888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grimwade, D., Hills, R. K., Moorman, A. V., Walker, H., Chatters, S., Goldstone, A. H., et al. (2010). Refinement of cytogenetic classification in acute myeloid leukemia: Determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood, 116, 354–365.

    Article  CAS  PubMed  Google Scholar 

  • Growney, J. D., Shigematsu, H., Li, Z., Lee, B. H., Adelsperger, J., Rowan, R., et al. (2005). Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood, 106, 494–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo, H., Ma, O., Speck, N. A., & Friedman, A. D. (2012). Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesis. Blood, 119, 4408–4418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guzman, M. L., & Allan, J. N. (2014). Concise review: Leukemia stem cells in personalized medicine. Stem Cells, 32, 844–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haase, D., Feuring-Buske, M., Konemann, S., Fonatsch, C., Troff, C., Verbeek, W., et al. (1995). Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations. Blood, 86, 2906–2912.

    CAS  PubMed  Google Scholar 

  • Haferlach, C., Dicker, F., Herholz, H., Schnittger, S., Kern, W., & Haferlach, T. (2008). Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia, 22, 1539–1541.

    Article  CAS  PubMed  Google Scholar 

  • Haferlach, C., Dicker, F., Kohlmann, A., Schindela, S., Weiss, T., Kern, W., et al. (2010). AML with CBFB-MYH11 rearrangement demonstrate RAS pathway alterations in 92 % of all cases including a high frequency of NF1 deletions. Leukemia, 24, 1065–1069.

    Article  CAS  PubMed  Google Scholar 

  • Han, E., Lee, H., Kim, M., Kim, Y., Han, K., Lee, S. E., et al. (2014). Characteristics of hematologic malignancies with coexisting t(9;22) and inv(16) chromosomal abnormalities. Blood Research, 49, 22–28.

    Google Scholar 

  • Hessels, D., & Schalken, J. A. (2013). Recurrent gene fusions in prostate cancer: Their clinical implications and uses. Current Urology Reports, 14, 214–222.

    Article  PubMed  Google Scholar 

  • Huang, H., Woo, A. J., Waldon, Z., Schindler, Y., Moran, T. B., Zhu, H. H., et al. (2012). A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation. Genes & Development, 26, 1587–1601.

    Article  CAS  Google Scholar 

  • Hyde, R. K., Zhao, L., Alemu, L., & Liu, P. P. (2015). Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice. Leukemia, 29, 1771–1778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikebe, M., Komatsu, S., Woodhead, J. L., Mabuchi, K., Ikebe, R., Saito, J., et al. (2001). The tip of the coiled-coil rod determines the filament formation of smooth muscle and nonmuscle myosin. The Journal of Biological Chemistry, 276, 30293–30300 Epub 2001 Jun 6.

    Article  CAS  PubMed  Google Scholar 

  • Illendula, A., Pulikkan, J. A., Zong, H., Grembecka, J., Xue, L., Sen, S., et al. (2015). Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFbeta-SMMHC delays leukemia in mice. Science, 347, 779–784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Illendula, A., Gilmour, J., Grembecka, J., Srimath Tirumala, V., Boulton, A., Kuntimaddi, A., et al. (2016). Small molecule inhibitor of CBFβ-RUNX binding for RUNX transcription factor driven cancers. eBioMedicine, 8, 117–131.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jane-Valbuena, J., Widlund, H. R., Perner, S., Johnson, L. A., Dibner, A. C., lin, W. M., et al. (2010). An oncogenic role for ETV1 in melanoma. Cancer Research, 70, 2075–2084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jongen-Lavrencic, M., Sun, S. M., Dijkstra, M. K., Valk, P. J., & Lowenberg, B. (2008). MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood, 111, 5078–5085.

    Article  CAS  PubMed  Google Scholar 

  • Kamikubo, Y., Zhao, L., Wunderlich, M., Corpora, T., Hyde, R. K., Paul, T. A., et al. (2010). Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1. Cancer Cell, 17, 455–468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kihara, R., Nagata, Y., Kiyoi, H., Kato, T., Yamamoto, E., Suzuki, K., et al. (2014). Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia, 28, 1586–1595.

    Article  CAS  PubMed  Google Scholar 

  • Kim, H. G., Kojima, K., Swindle, C. S., Cotta, C. V., Huo, Y., Reddy, V., & Klug, C. A. (2008). FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia. Blood, 111, 1567–1574.

    Google Scholar 

  • Kottaridis, P. D., Gale, R. E., Langabeer, S. E., Frew, M. E., Bowen, D. T., & Linch, D. C. (2002). Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: Implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood, 100, 2393–2398.

    Article  CAS  PubMed  Google Scholar 

  • Kummalue, T., Lou, J., & Friedman, A. D. (2002). Multimerization via its myosin domain facilitates nuclear localization and inhibition of core binding factor (CBF) activities by the CBFbeta-smooth muscle myosin heavy chain myeloid leukemia oncoprotein. Molecular and Cellular Biology, 22, 8278–8291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuo, Y. H., Landrette, S. F., Heilman, S. A., Perrat, P. N., Garrett, L., Liu, P. P., et al. (2006). Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell, 9, 57–68.

    Article  CAS  PubMed  Google Scholar 

  • Kuo, Y. H., Gerstein, R. M., & Castilla, L. H. (2008). Cbfbeta-SMMHC impairs differentiation of common lymphoid progenitors and reveals an essential role for RUNX in early B-cell development. Blood, 111, 1543–1551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuo, Y. H., Zaidi, S. K., Gornostaeva, S., Komori, T., Stein, G. S., & Castilla, L. H. (2009). Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. Blood, 113, 3323–3332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ladanyi, M. (1995). The emerging molecular genetics of sarcoma translocations. Diagnostic Molecular Pathology, 4, 162–173.

    Article  CAS  PubMed  Google Scholar 

  • Le Beau, M. M., Larson, R. A., Bitter, M. A., Vardiman, J. W., Golomb, H. M., & Rowley, J. D. (1983). Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. A unique cytogenetic-clinicopathological association. New England Journal of Medicine, 309, 630–636.

    Article  CAS  PubMed  Google Scholar 

  • Li, Z., Lu, J., Sun, M., Mi, S., Zhang, H., Luo, R. T., et al. (2008). Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proceedings of the National Academy of Sciences of the United States of America, 105, 15535–15540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, P., Claxton, D. F., Marlton, P., Hajra, A., Siciliano, J., Freedman, M., et al. (1993a). Identification of yeast artificial chromosomes containing the inversion 16 p-arm breakpoint associated with acute myelomonocytic leukemia. Blood, 82, 716–721.

    CAS  PubMed  Google Scholar 

  • Liu, P., Tarle, S. A., Hajra, A., Claxton, D. F., Marlton, P., Freedman, M., et al. (1993b). Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science, 261, 1041–1044.

    Article  CAS  PubMed  Google Scholar 

  • Liu, P. P., Hajra, A., Wijmenga, C., & Collins, F. S. (1995). Molecular pathogenesis of the chromosome 16 inversion in the M4Eo subtype of acute myeloid leukemia. [see comments]. [erratum appears in Blood 1997 Mar 1;89(5):1842]. Blood, 85, 2289–2302.

    Google Scholar 

  • Liu, P. P., Wijmenga, C., Hajra, A., Blake, T. B., Kelley, C. A., Adelstein, R. S., Bagg, A., Rector, J., Cotelingam, J., Willman, C. L., & Collins, F. S. (1996). Identification of the chimeric protein product of the CBFB-MYH11 fusion gene in inv(16) leukemia cells. [erratum appears in Genes Chromosomes Cancer 1997 Jan;18(1):71]. Genes, Chromosomes & Cancer, 16, 77–87.

    Google Scholar 

  • Look, A. T. (1997). Oncogenic transcription factors in the human acute leukemias. Science, 278, 1059–1064.

    Article  CAS  PubMed  Google Scholar 

  • Lukasik, S. M., Zhang, L., Corpora, T., Tomanicek, S., Li, Y., Kundu, M., et al. (2002). Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis. Nature Structural Biology, 9, 674–679.

    Article  CAS  PubMed  Google Scholar 

  • Markus, J., Garin, M. T., Bies, J., Galili, N., Raza, A., Thirman, M. J., et al. (2007). Methylation-independent silencing of the tumor suppressor INK4b (p15) by CBFbeta-SMMHC in acute myelogenous leukemia with inv(16) . Cancer Research, 67, 992–1000.

    Google Scholar 

  • Mchale, C. M., Wiemels, J. L., Zhang, L., Ma, X., Buffler, P. A., Feusner, J., et al. (2003). Prenatal origin of childhood acute myeloid leukemias harboring chromosomal rearrangements t(15;17) and inv(16) . Blood, 101, 4640–4641.

    Google Scholar 

  • Mehrotra, B., George, T. I., Kavanau, K., Avet-Loiseau, H., Moore 2nd, D., Willman, C. L., et al. (1995). Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia. Blood, 86, 1139–1147.

    CAS  PubMed  Google Scholar 

  • Miano, J. M., Cserjesi, P., Ligon, K. L., Periasamy, M., & Olson, E. N. (1994). Smooth muscle myosin heavy chain exclusively marks the smooth muscle lineage during mouse embryogenesis. Circulation Research, 75, 803–812.

    Article  CAS  PubMed  Google Scholar 

  • Miyazaki, M., Naito, H., Sugimoto, Y., Yoshida, K., Kawato, H., Okayama, T., et al. (2013). Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors. Bioorganic & Medicinal Chemistry, 21, 4319–4331.

    Article  CAS  Google Scholar 

  • Monma, F., Nishii, K., Shiga, J., Sugahara, H., Lorenzo, F. T., Watanabe, Y., et al. (2007). Detection of the CBFB/MYH11 fusion gene in de novo acute myeloid leukemia (AML): A single-institution study of 224 Japanese AML patients. Leukemia Research, 31, 471–476.

    Article  CAS  PubMed  Google Scholar 

  • Nakano, Y., Kiyoi, H., Miyawaki, S., Asou, N., Ohno, R., Saito, H., & Naoe, T. (1999). Molecular evolution of acute myeloid leukaemia in relapse: Unstable N-ras and FLT3 genes compared with p53 gene. British Journal of Haematology, 104, 659–664.

    Article  CAS  PubMed  Google Scholar 

  • Oh, S., Shin, S., & Janknecht, R. (2012). ETV1, 4 and 5: An oncogenic subfamily of ETS transcription factors. Biochimica et Biophysica Acta, 1826, 1–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okuda, T., Van Deursen, J., Hiebert, S. W., Grosveld, G., & Downing, J. R. (1996). AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell, 84, 321–330.

    Article  CAS  PubMed  Google Scholar 

  • Opatz, S., Polzer, H., Herold, T., Konstandin, N. P., Ksienzyk, B., Zellmeier, E., et al. (2013). Exome sequencing identifies recurring FLT3 N676 K mutations in core-binding factor leukemia. Blood, 122, 1761–1769.

    Article  CAS  PubMed  Google Scholar 

  • Park, T. S., Lee, S. T., Song, J., Lee, K. A., Lee, J. H., Kim, J., et al. (2009). Detection of a novel CBFB/MYH11 variant fusion transcript (K-type) showing partial insertion of exon 6 of CBFB gene using two commercially available multiplex RT-PCR kits. Cancer Genetics and Cytogenetics, 189, 87–92.

    Article  CAS  PubMed  Google Scholar 

  • Paschka, P., Marcucci, G., Ruppert, A. S., Mrozek, K., Chen, H., Kittles, R. A., et al. (2006). Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): A Cancer and Leukemia Group B Study. Journal of Clinical Oncology, 24, 3904–3911.

    Google Scholar 

  • Paschka, P., Du, J., Schlenk, R. F., Gaidzik, V. I., Bullinger, L., Corbacioglu, A., et al. (2013). Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): A study of the German-Austrian AML Study Group (AMLSG). Blood, 121, 170–177.

    Google Scholar 

  • Pulsoni, A., Iacobelli, S., Bernardi, M., Borgia, M., Camera, A., Cantore, N., et al. (2008). M4 acute myeloid leukemia: The role of eosinophilia and cytogenetics in treatment response and survival. The GIMEMA experience. Haematologica, 93, 1025–1032.

    Article  CAS  PubMed  Google Scholar 

  • Qi, J., Singh, S., Hua, W. K., Cai, Q., Chao, S. W., Li, L., et al. (2015). HDAC8 inhibition specifically targets inv(16) acute myeloid leukemic stem cells by restoring p53 acetylation. Cell Stem Cell, 17, 597–610.

    Google Scholar 

  • Ravandi, F., Burnett, A. K., Agura, E. D., & Kantarjian, H. M. (2007). Progress in the treatment of acute myeloid leukemia. Cancer, 110, 1900–1910.

    Article  CAS  PubMed  Google Scholar 

  • Sasaki, K., Yagi, H., Bronson, R. T., Tominaga, K., Matsunashi, T., Deguchi, K., et al. (1996). Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta. Proceedings of the National Academy of Sciences of the United States of America, 93, 12359–12363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwind, S., Edwards, C. G., Nicolet, D., Mrozek, K., Maharry, K., wu, Y. Z., et al. (2013). inv(16) /t(16;16) acute myeloid leukemia with non-type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations. Blood, 121, 385–391.

    Google Scholar 

  • Secker-Walker, L. M., Morgan, G. J., Min, T., Swansbury, G. J., Craig, J., Yamada, T., et al. (1992). Inversion of chromosome 16 with the Philadelphia chromosome in acute myelomonocytic leukemia with eosinophilia. Report of two cases. Cancer Genetics and Cytogenetics, 58, 29–34.

    Article  CAS  PubMed  Google Scholar 

  • Seifert, H., Mohr, B., Thiede, C., Oelschlagel, U., Schakel, U., Illmer, T., et al. (2009). The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. Leukemia, 23, 656–663.

    Article  CAS  PubMed  Google Scholar 

  • Seo, W., Ikawa, T., Kawamoto, H., & Taniuchi, I. (2012). Runx1-Cbfbeta facilitates early B lymphocyte development by regulating expression of Ebf1. The Journal of Experimental Medicine, 209, 1255–1262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shigesada, K., Van De Sluis, B., & Liu, P. P. (2004). Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11. Oncogene, 23, 4297–4307.

    Google Scholar 

  • Shih, L. Y., Liang, D. C., Huang, C. F., Chang, Y. T., Lai, C. L., Lin, T. H., et al. (2008). Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia, 22, 303–307.

    Article  CAS  PubMed  Google Scholar 

  • Shlush, L. I., Zandi, S., Mitchell, A., Chen, W. C., Brandwein, J. M., Gupta, V., et al. (2014). Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature, 506, 328–333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sohn, R. L., Vikstrom, K. L., Strauss, M., Cohen, C., Szent-Gyorgyi, A. G., & leinwand, L. A. (1997). A 29 residue region of the sarcomeric myosin rod is necessary for filament formation. Journal of Molecular Biology, 266, 317–330.

    Article  CAS  PubMed  Google Scholar 

  • Song, J., Mercer, D., Hu, X., Liu, H., & Li, M. M. (2011). Common leukemia- and lymphoma-associated genetic aberrations in healthy individuals. The Journal of Molecular Diagnostics, 13, 213–219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sood, R., Hansen, N. F., Donovan, F. X., Carrington, B., Bucci, D., Maskeri, B., et al. (2016). Somatic mutational landscape of AML with inv(16) or t(8;21) identifies patterns of clonal evolution in relapse leukemia. Leukemia, 30, 501–504.

    Google Scholar 

  • Swerdlow, S. H., Campo, E., Harris, N. L., Jaffe, E. S., Pileri, S. A., Stein, H., et al. (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. In OMS (Ed.), WHO classification of tumours of haematopoietic and lymphoid tissues (4th ed.). Lyon: World Health Organization.

    Google Scholar 

  • Valk, P. J., Verhaak, R. G., Beijen, M. A., Erpelinck, C. A., Barjesteh Van Waalwijk Van Doorn-Khosrovani, S., Boer, J. M., et al. (2004). Prognostically useful gene-expression profiles in acute myeloid leukemia. The New England Journal of Medicine, 350, 1617–1628.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Q., Stacy, T., Binder, M., Marin-Padilla, M., Sharpe, A. H., & Speck, N. A. (1996a). Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proceedings of the National Academy of Sciences of the United States of America, 93, 3444–3449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, Q., Stacy, T., Miller, J. D., Lewis, A. F., Gu, T. L., Huang, X., et al. (1996b). The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell, 87, 697–708.

    Article  CAS  PubMed  Google Scholar 

  • Wee, H. J., Voon, D. C., Bae, S. C., & Ito, Y. (2008). PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: Implications for leukemogenesis. Blood, 112, 3777–3787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu, Y., Slovak, M. L., Snyder, D. S., & Arber, D. A. (2006). Coexistence of inversion 16 and the Philadelphia chromosome in acute and chronic myeloid leukemias: Report of six cases and review of literature. American Journal of Clinical Pathology, 125, 260–266.

    Article  PubMed  Google Scholar 

  • Xue, L., Pulikkan, J. A., Valk, P. J., & Castilla, L. H. (2014). NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing Cbfbeta-SMMHC via activation of MEK/ERK axis. Blood, 124, 426–436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, D. E., Hetherington, C. J., Meyers, S., Rhoades, K. L., Larson, C. J., Chen, H. M., et al. (1996). CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Molecular and Cellular Biochemistry, 16, 1231–1240.

    Article  CAS  Google Scholar 

  • Zhang, L., D’costa, J., Kummalue, T., Civin, C. I., & Friedman, A. D. (2006). Identification of a region on the outer surface of the CBFbeta-SMMHC myeloid oncoprotein assembly competence domain critical for multimerization. Oncogene, 25, 7289–7296.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, Z., Ding, Q., Liu, J. J., Zhang, J., Jiang, N., Chu, X. J., et al. (2014). Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy. Bioorganic & Medicinal Chemistry, 22, 4001–4009.

    Article  CAS  Google Scholar 

  • Zhao, L., Cannons, J. L., Anderson, S., Kirby, M., Xu, L., Castilla, L. H., et al. (2007). CBFB-MYH11 hinders early T-cell development and induces massive cell death in the thymus. Blood, 109, 3432–3440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao, L., Melenhorst, J. J., Alemu, L., Kirby, M., Anderson, S., Kench, M., et al. (2012). KIT with D816 mutations cooperates with CBFB-MYH11 for leukemogenesis in mice. Blood, 119, 1511–1521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao, Y., Yu, S., Sun, W., Liu, L., Lu, J., Mceachern, D., et al. (2013). A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice. Journal of Medicinal Chemistry, 56, 5553–5561.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Lucio H. Castilla

  2. Molecular Physiology and Biophysics, University of Virginia Medical School, Charlottesville, VA, 22908, USA

    John H. Bushweller

Authors
  1. Lucio H. Castilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John H. Bushweller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lucio H. Castilla .

Editor information

Editors and Affiliations

  1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Yoram Groner

  2. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Yoshiaki Ito

  3. Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA

    Paul Liu

  4. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom

    James C. Neil

  5. Department of Cell and Development Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Nancy A. Speck

  6. Mayo Clinic, Rochester, Minnesota, USA

    Andre van Wijnen

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Castilla, L.H., Bushweller, J.H. (2017). Molecular Basis and Targeted Inhibition of CBFβ-SMMHC Acute Myeloid Leukemia. In: Groner, Y., Ito, Y., Liu, P., Neil, J., Speck, N., van Wijnen, A. (eds) RUNX Proteins in Development and Cancer. Advances in Experimental Medicine and Biology, vol 962. Springer, Singapore. https://doi.org/10.1007/978-981-10-3233-2_15

Download citation

Publish with us

Policies and ethics

Search

Navigation