Browse > Article
http://dx.doi.org/10.14348/molcells.2020.0010

RUNX1 Mutations in the Leukemic Progression of Severe Congenital Neutropenia  

Olofsen, Patricia A. (Department of Hematology, Erasmus MC)
Touw, Ivo P. (Department of Hematology, Erasmus MC)
Publication Information
Molecules and Cells / v.43, no.2, 2020 , pp. 139-144 More about this Journal
Abstract
Somatic RUNX1 mutations are found in approximately 10% of patients with de novo acute myeloid leukemia (AML), but are more common in secondary forms of myelodysplastic syndrome (MDS) or AML. Particularly, this applies to MDS/AML developing from certain types of leukemia-prone inherited bone marrow failure syndromes. How these RUNX1 mutations contribute to the pathobiology of secondary MDS/AML is still unknown. This mini-review focusses on the role of RUNX1 mutations as the most common secondary leukemogenic hit in MDS/AML evolving from severe congenital neutropenia (SCN).
Keywords
leukemic progression; RUNX1; severe congenital neutropenia;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Osato, M. (2004). Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene 23, 4284-4296.   DOI
2 Papapetrou, E.P. (2019). Modeling myeloid malignancies with patientderived iPSCs. Exp. Hematol. 71, 77-84.   DOI
3 Preudhomme, C., Warot-Loze, D., Roumier, C., Grardel-Duflos, N., Garand, R., Lai, J.L., Dastugue, N., Macintyre, E., Denis, C., Bauters, F., et al. (2000). High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood 96, 2862-2869.   DOI
4 Quentin, S., Cuccuini, W., Ceccaldi, R., Nibourel, O., Pondarre, C., Pagès, M.P., Vasquez, N., Dubois d'Enghien, C., Larghero, J., Peffault, de Latour, R., et al. (2011). Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions. Blood 117, e161-e170.   DOI
5 Rosenberg, P.S., Alter, B.P., Bolyard, A.A., Bonilla, M.A., Boxer, L.A., Cham, B., Fier, C., Freedman, M., Kannourakis, G., Kinsey, S., et al. (2006). The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 107, 4628-4635.   DOI
6 Harada, Y., Inoue, D., Ding, Y., Imagawa, J., Doki, N., Matsui, H., Yahata, T., Matsushita, H., Ando, K., Sashida, G., et al. (2013). RUNX1/AML1 mutant collaborates with BMI1 overexpression in the development of human and murine myelodysplastic syndromes. Blood 121, 3434-3446.   DOI
7 Hermans, M.H., Antonissen, C., Ward, A.C., Mayen, A.E., Ploemacher, R.E., and Touw, I.P. (1999). Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene. J. Exp. Med. 189, 683-692.   DOI
8 Hermans, M.H., Ward, A.C., Antonissen, C., Karis, A., Lowenberg, B., and Touw, I.P. (1998). Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia. Blood 92, 32-39.   DOI
9 Ko, M., An, J., Bandukwala, H.S., Chavez, L., Aijo, T., Pastor, W.A., Segal, M.F., Li, H., Koh, K.P., Lähdesmäki, H., et al. (2013). Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature 497, 122-126.   DOI
10 Hino, S., Kishida, S., Michiue, T., Fukui, A., Sakamoto, I., Takada, S., Asashima, M., and Kikuchi, A. (2001). Inhibition of the Wnt signaling pathway by Idax, a novel Dvl-binding protein. Mol. Cell. Biol. 21, 330-342.   DOI
11 Liu, F., Kunter, G., Krem, M.M., Eades, W.C., Cain, J.A., Tomasson, M.H., Hennighausen, L., and Link, D.C. (2008). Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5. J. Clin. Invest. 118, 946-955.   DOI
12 Mangan, J.K. and Speck, N.A. (2011). RUNX1 mutations in clonal myeloid disorders: from conventional cytogenetics to next generation sequencing, a story 40 years in the making. Crit. Rev. Oncog. 16, 77-91.   DOI
13 Song, W.J., Sullivan, M.G., Legare, R.D., Hutchings, S., Tan, X., Kufrin, D., Ratajczak, J., Resende, I.C., Haworth, C., Hock, R., et al. (1999). Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat. Genet. 23, 166-175.   DOI
14 Rosenberg, P.S., Zeidler, C., Bolyard, A.A., Alter, B.P., Bonilla, M.A., Boxer, L.A., Dror, Y., Kinsey, S., Link, D.C., Newburger, P.E., et al. (2010). Stable longterm risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br. J. Haematol. 150, 196-199.   DOI
15 Sakurai, M., Kunimoto, H., Watanabe, N., Fukuchi, Y., Yuasa, S., Yamazaki, S., Nishimura, T., Sadahira, K., Fukuda, K., Okano, H., et al. (2014). Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients. Leukemia 28, 2344-2354.   DOI
16 Schnittger, S., Dicker, F., Kern, W., Wendland, N., Sundermann, J., Alpermann, T., Haferlach, C., and Haferlach, T. (2011). RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood 117, 2348-2357.   DOI
17 Skokowa, J., Dale, D.C., Touw, I.P., Zeidler, C., and Welte, K. (2017). Severe congenital neutropenias. Nat. Rev. Dis. Primers 3, 17032.   DOI
18 Skokowa, J., Steinemann, D., Katsman-Kuipers, J.E., Zeidler, C., Klimenkova, O., Klimiankou, M., Unalan, M., Kandabarau, S., Makaryan, V., Beekman, R., et al. (2014). Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 123, 2229-2237.   DOI
19 Sood, R., Kamikubo, Y., and Liu, P. (2017). Role of RUNX1 in hematological malignancies. Blood 129, 2070-2082.   DOI
20 Antony-Debre, I., Manchev, V.T., Balayn, N., Bluteau, D., Tomowiak, C., Legrand, C., Langlois, T., Bawa, O., Tosca, L., Tachdjian, G., et al. (2015). Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia. Blood 125, 930-940.   DOI
21 Watanabe-Okochi, N., Kitaura, J., Ono, R., Harada, H., Harada, Y., Komeno, Y., Nakajima, H., Nosaka, T., Inaba, T., and Kitamura, T. (2008). AML1 mutations induced MDS and MDS/AML in a mouse BMT model. Blood 111, 4297-4308.   DOI
22 Steensma, D.P., Gibbons, R.J., Mesa, R.A., Tefferi, A., and Higgs, DR. (2005). Somatic point mutations in RUNX1/CBFA2/AML1 are common in highrisk myelodysplastic syndrome, but not in myelofibrosis with myeloid metaplasia. Eur. J. Haematol. 74, 47-53.   DOI
23 Tang, J.L., Hou, H.A., Chen, C.Y., Liu, C.Y., Chou, W.C., Tseng, M.H., Huang, C.F., Lee, F.Y., Liu, M.C., Yao, M., et al. (2009). AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 114, 5352-5361.   DOI
24 Touw, I.P. (2015). Game of clones: the genomic evolution of severe congenital neutropenia. Hematology Am. Soc. Hematol. Educ. Program 2015, 1-7.   DOI
25 Yzaguirre, A.D., de Bruijn, M.F., and Speck, N.A. (2017). The role of Runx1 in embryonic blood cell formation. Adv. Exp. Med. Biol. 962, 47-64.   DOI
26 Zhu, Q.S., Xia, L., Mills, G.B., Lowell, C.A., Touw, I.P., and Corey, S.J. (2006). G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth. Blood 107, 1847-1856.   DOI
27 Chen, C.Y., Lin, L.I., Tang, J.L., Ko, B.S., Tsay, W., Chou, W.C., Yao, M., Wu, S.J., Tseng, M.H., and Tien, H.F. (2007). RUNX1 gene mutation in primary myelodysplastic syndrome--the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br. J. Haematol. 139, 405-414.   DOI
28 Beekman, R., Valkhof, M.G., Sanders, M.A., van Strien, P.M., Haanstra, J.R., Broeders, L., Geertsma-Kleinekoort, W.M., Veerman, A.J., Valk, P.J., Verhaak, R.G., et al. (2012). Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia. Blood 119, 5071-5077.   DOI
29 Bellissimo, D.C. and Speck, N.A. (2017). RUNX1 mutations in inherited and sporadic leukemia. Front. Cell Dev. Biol. 5, 111.   DOI
30 Cai, X., Gaudet, J.J., Mangan, J.K., Chen, M.J., De Obaldia, M.E., Oo, Z., Ernst, P., and Speck, N.A. (2011). Runx1 loss minimally impacts long-term hematopoietic stem cells. PLoS One 6, e28430.   DOI
31 Chin, D.W., Watanabe-Okochi, N., Wang, C.Q., Tergaonkar, V., and Osato, M. (2015). Mouse models for core binding factor leukemia. Leukemia 29, 1970-1980.   DOI
32 Christiansen, D.H., Andersen, M.K., and Pedersen-Bjergaard, J. (2004). Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood 104, 1474-1481.
33 Harada, Y. and Harada, H. (2009). Molecular pathways mediating MDS/AML with focus on AML1/RUNX1 point mutations. J. Cell. Physiol. 220, 16-20.   DOI
34 Connelly, J.P., Kwon, E.M., Gao, Y., Trivedi, N.S., Elkahloun, A.G., Horwitz, M.S., Cheng, L., and Liu, P.P. (2014). Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects. Blood 124, 1926-1930.
35 Dale, D.C., Bonilla, M.A., Davis, M.W., Nakanishi, A.M., Hammond, W.P., Kurtzberg, J., Wang, W., Jakubowski, A., Winton, E., Lalezari, P., et al. (1993). A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood 81, 2496-2502.   DOI
36 Gaidzik, V.I., Bullinger, L., Schlenk, R.F., Zimmermann, A.S., Rock, J., Paschka, P., Corbacioglu, A., Krauter, J., Schlegelberger, B., Ganser, A., et al. (2011). RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J. Clin. Oncol. 29, 1364-1372.   DOI
37 Germeshausen, M., Ballmaier, M., and Welte, K. (2007). Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: results of a long-term survey. Blood 109, 93-99.   DOI
38 Goyama, S., Schibler, J., Cunningham, L., Zhang, Y., Rao, Y., Nishimoto, N., Nakagawa, M., Olsson, A., Wunderlich, M., Link, K.A., et al. (2013). Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. J. Clin. Invest. 123, 3876-3888.   DOI
39 Harada, H., Harada, Y., Niimi, H., Kyo, T., Kimura, A., and Inaba, T. (2004). High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 103, 2316-2324.   DOI
40 Harada, H., Harada, Y., Tanaka, H., Kimura, A., and Inaba, T. (2003). Implications of somatic mutations in the AML1 gene in radiationassociated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood 101, 673-680.   DOI
41 Olofsen, P.A., van Strien, P.M.H., Roovers, O., de Looper, H.W.J., Hoogenboezem, R.M., Bosch, D.A., Ghazvini, M., Bindels, E.M.J., de Pater, E.M., and Touw, I.P. (2019). PML plays a key role in severe congenital neutropenia with mutant elane causing neutrophil elastase protein misfolding. Blood 134, 213.   DOI
42 Olofsen, P.A., Fatrai, S., van Strien, P.M.H., Obenauer, J.C., Hoogenboezem, R.M., Erpelinck-Verschueren, C.A.J., Roovers, O., Haferlach, T., Valk, P., Schneider, R.K., et al. (2018). A leukemic progression model of severe congenital neutropenia uncovers a novel mechanism of AML development involving elevated inflammatory responses, mutation of CXXC4 and decreased TET2 levels. Blood 132, 540.   DOI