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Paulina Podszywalow-Bartnicka\*, Magdalena Wolczyk and Katarzyna Piwocka Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland

\*Address all correspondence to: p.podszywalow@nencki.edu.pl

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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[95] Hofman IJF, van Duin M, De Bruyne E, Fancello L, Mulligan G, Geerdens E, et al. RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response. Leukemia. 2017;**31**(8):1706-1714. DOI: 10.1038/ leu.2016.370

[96] De Keersmaecker K, Atak ZK, Li N, Vicente C, Patchett S, Girardi T, et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nature Genetics. 2013 Feb;**45**(2):186-190. DOI: 10.1038/ ng.2508

[97] Kampen KR, Fancello L, Girardi T, Rinaldi G, Planque M, Sulima SO, et al. Translatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells. Nat Commun. 2019, 2542;**10**(1). DOI: 10.1038/s41467-019-10508-2

[98] Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, et al. Identification of RPS14 as a 5qsyndrome gene by RNA interference screen. Nature. 2008 Jan 17;**451**(7176):335-339. DOI: 10.1038/ nature06494

[99] Rao S, Lee S-Y, Gutierrez A, Perrigoue J, Thapa RJ, Tu Z, et al. Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B. Blood. 2012 Nov 1;**120**(18):3764-3773. DOI: 10.1182/blood-2012-03-415349

[100] Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015 Oct

22;**526**(7574):525-530. DOI: 10.1038/ nature15395

[101] Ljungström V, Cortese D, Young E, Pandzic T, Mansouri L, Plevova K, et al. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations. Blood. 2016 Feb 25;**127**(8):1007-1016. DOI: 10.1182/blood-2015-10-674572

[102] Shi Z, Fujii K, Kovary KM, Genuth NR, Röst HL, Teruel MN, et al. Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide. Molecular Cell. 2017 Jul 6;**67**(1):71-83.e7. DOI: 10.1016/j. molcel.2017.05.021

[103] Bhat P, Shwetha S, Sharma DK, Joseph AP, Srinivasan N, Das S. The beta hairpin structure within ribosomal protein S5 mediates interplay between domains II and IV and regulates HCV IRES function. Nucleic Acids Research. 2015 Mar 11;**43**(5):2888-2901. DOI: 10.1093/nar/gkv110

[104] Hertz MI, Landry DM, Willis AE, Luo G, Thompson SR. Ribosomal protein S25 dependency reveals a common mechanism for diverse internal ribosome entry sites and ribosome shunting. Molecular and Cellular Biology. 2013 Mar;**33**(5):1016-1026. DOI: 10.1128/MCB.00879-12

[105] Meyuhas O. Ribosomal Protein S6 Phosphorylation. Four Decades of Research. Int Rev Cell Mol Biol. 2015;**320**:41-73. DOI: 10.1016/ bs.ircmb.2015.07.006

[106] Myasnikov AG, Kundhavai Natchiar S, Nebout M, Hazemann I, Imbert V, Khatter H, et al. Structurefunction insights reveal the human ribosome as a cancer target for antibiotics. Nature Communications. 2016 Sep 26;**7**:12856. DOI: 10.1038/ncomms12856

**285**

*Targeting of Post-Transcriptional Regulation as Treatment Strategy in Acute Leukemia*

Cancer Discovery. 2016 Jan;**6**(1):59-70. DOI: 10.1158/2159-8290.CD-14-0673

Baladandayuthapani V, Lin H, He J, Jones RJ, et al. RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma. British Journal of Haematology. 2017;**177**(1):80-94. DOI:

[114] Lee HC, Wang H,

10.1111/bjh.14525

[115] Khot A, Brajanovski N,

Cameron DP, Hein N, Maclachlan KH, Sanij E, et al. First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Cancer Discovery. 2019;**9**(8):1036-1049. DOI: 10.1158/2159-8290.CD-18-1455

*DOI: http://dx.doi.org/10.5772/intechopen.94421*

contributes to imatinib sensitivity by blocking the EphB4/RhoA pathway in chronic myeloid leukemia cell lines. Med Oncol Northwood Lond Engl. 2014 Feb;**31**(2):836. DOI: 10.1007/

[108] Tujebajeva RM, Graifer DM, Karpova GG, Ajtkhozhina NA. Alkaloid

[109] Lü S, Wang J. Homoharringtonine

Natchiar K, Biondani G, Loeffelholz O von, Holvec S, et al. Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies. Cell 2020 Mar 5;9(3). DOI:

Park GY, Murai J, Koch CE, Eisen TJ, et al. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nature Medicine. 2017 Apr;**23**(4):461-

[112] Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancerspecific activation of p53. Cancer Cell. 2012 Jul 10;**22**(1):51-65. DOI: 10.1016/j.

[113] Devlin JR, Hannan KM, Hein N, Cullinane C, Kusnadi E, Ng PY, et al. Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma.

homoharringtonine inhibits polypeptide chain elongation on human ribosomes on the step of peptide bond formation. FEBS Letters. 1989 Nov 6;**257**(2):254-256. DOI: 10.1016/0014-5793(89)81546-7

and omacetaxine for myeloid hematological malignancies. Journal of Hematology & Oncology. 2014 Jan 3;**7**(2). DOI: 10.1186/1756-8722-7-2

[110] Gilles A, Frechin L,

10.3390/cells9030629

[111] nBruno PM, Liu Y,

471. DOI: 10.1038/nm.4291

ccr.2012.05.019

s12032-013-0836-9

[107] Huang B-T, Zeng Q-C, Zhao W-H, Tan Y. Homoharringtonine *Targeting of Post-Transcriptional Regulation as Treatment Strategy in Acute Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94421*

contributes to imatinib sensitivity by blocking the EphB4/RhoA pathway in chronic myeloid leukemia cell lines. Med Oncol Northwood Lond Engl. 2014 Feb;**31**(2):836. DOI: 10.1007/ s12032-013-0836-9

*Acute Leukemias*

leu.2016.370

ng.2508

Diamond-Blackfan Anemia and Promotes Lymphomagenesis. Cell Reports. 2015 Oct 27;**13**(4):712-722. DOI: 10.1016/j.celrep.2015.09.038

22;**526**(7574):525-530. DOI: 10.1038/

[102] Shi Z, Fujii K, Kovary KM, Genuth NR, Röst HL, Teruel MN, et al. Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide. Molecular Cell. 2017 Jul 6;**67**(1):71-83.e7. DOI: 10.1016/j.

[103] Bhat P, Shwetha S, Sharma DK, Joseph AP, Srinivasan N, Das S. The beta hairpin structure within ribosomal protein S5 mediates interplay between domains II and IV and regulates HCV IRES function. Nucleic Acids Research. 2015 Mar 11;**43**(5):2888-2901. DOI:

[104] Hertz MI, Landry DM, Willis AE, Luo G, Thompson SR. Ribosomal protein S25 dependency reveals a

common mechanism for diverse internal ribosome entry sites and ribosome shunting. Molecular and Cellular Biology. 2013 Mar;**33**(5):1016-1026. DOI: 10.1128/MCB.00879-12

[105] Meyuhas O. Ribosomal Protein S6 Phosphorylation. Four Decades of Research. Int Rev Cell Mol Biol. 2015;**320**:41-73. DOI: 10.1016/

[106] Myasnikov AG, Kundhavai Natchiar S, Nebout M, Hazemann I, Imbert V, Khatter H, et al. Structurefunction insights reveal the human ribosome as a cancer target for antibiotics. Nature Communications. 2016 Sep 26;**7**:12856. DOI: 10.1038/ncomms12856

[107] Huang B-T, Zeng Q-C, Zhao W-H, Tan Y. Homoharringtonine

molcel.2017.05.021

10.1093/nar/gkv110

bs.ircmb.2015.07.006

[101] Ljungström V, Cortese D, Young E, Pandzic T, Mansouri L, Plevova K, et al. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations. Blood. 2016 Feb 25;**127**(8):1007-1016. DOI: 10.1182/blood-2015-10-674572

nature15395

[95] Hofman IJF, van Duin M, De Bruyne E, Fancello L, Mulligan G, Geerdens E, et al. RPL5 on 1p22.1 is recurrently deleted in multiple myeloma

and its expression is linked to bortezomib response. Leukemia. 2017;**31**(8):1706-1714. DOI: 10.1038/

[96] De Keersmaecker K, Atak ZK, Li N, Vicente C, Patchett S, Girardi T, et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic

leukemia. Nature Genetics. 2013 Feb;**45**(2):186-190. DOI: 10.1038/

[97] Kampen KR, Fancello L, Girardi T, Rinaldi G, Planque M, Sulima SO, et al. Translatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells. Nat Commun. 2019, 2542;**10**(1). DOI: 10.1038/s41467-019-10508-2

[98] Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, et al. Identification of RPS14 as a 5qsyndrome gene by RNA interference

17;**451**(7176):335-339. DOI: 10.1038/

[99] Rao S, Lee S-Y, Gutierrez A, Perrigoue J, Thapa RJ, Tu Z, et al. Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B. Blood. 2012 Nov 1;**120**(18):3764-3773. DOI: 10.1182/blood-2012-03-415349

[100] Landau DA, Tausch E,

Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015 Oct

screen. Nature. 2008 Jan

nature06494

**284**

[108] Tujebajeva RM, Graifer DM, Karpova GG, Ajtkhozhina NA. Alkaloid homoharringtonine inhibits polypeptide chain elongation on human ribosomes on the step of peptide bond formation. FEBS Letters. 1989 Nov 6;**257**(2):254-256. DOI: 10.1016/0014-5793(89)81546-7

[109] Lü S, Wang J. Homoharringtonine and omacetaxine for myeloid hematological malignancies. Journal of Hematology & Oncology. 2014 Jan 3;**7**(2). DOI: 10.1186/1756-8722-7-2

[110] Gilles A, Frechin L, Natchiar K, Biondani G, Loeffelholz O von, Holvec S, et al. Targeting the Human 80S Ribosome in Cancer: From Structure to Function and Drug Design for Innovative Adjuvant Therapeutic Strategies. Cell 2020 Mar 5;9(3). DOI: 10.3390/cells9030629

[111] nBruno PM, Liu Y, Park GY, Murai J, Koch CE, Eisen TJ, et al. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nature Medicine. 2017 Apr;**23**(4):461- 471. DOI: 10.1038/nm.4291

[112] Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancerspecific activation of p53. Cancer Cell. 2012 Jul 10;**22**(1):51-65. DOI: 10.1016/j. ccr.2012.05.019

[113] Devlin JR, Hannan KM, Hein N, Cullinane C, Kusnadi E, Ng PY, et al. Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. Cancer Discovery. 2016 Jan;**6**(1):59-70. DOI: 10.1158/2159-8290.CD-14-0673

[114] Lee HC, Wang H, Baladandayuthapani V, Lin H, He J, Jones RJ, et al. RNA Polymerase I Inhibition with CX-5461 as a Novel Therapeutic Strategy to Target MYC in Multiple Myeloma. British Journal of Haematology. 2017;**177**(1):80-94. DOI: 10.1111/bjh.14525

[115] Khot A, Brajanovski N, Cameron DP, Hein N, Maclachlan KH, Sanij E, et al. First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Cancer Discovery. 2019;**9**(8):1036-1049. DOI: 10.1158/2159-8290.CD-18-1455

**287**

**Chapter 16**

**Abstract**

Leukemia

Mechanisms of Resistence of New

New drugs targeting single mutations have been recently approved for Acute Myeloid Leukemia (AML) treatment, but allogeneic transplant still remains the only curative option in intermediate and unfavorable risk settings, because of the high incidence of relapse. Molecular analysis repertoire permits the identification of the target mutations and drives the choice of target drugs, but the etherogeneity of the disease reduces the curative potential of these agents. Primary and secondary AML resistance to new target agents is actually an intriguing issue and some of these mechanisms have already been explored and identified. Changes in mutations, release of microenvironment factors competing for the same therapeutic target or promoting the survival of blasts or of the leukemic stem cell, the upregulation of the target-downstream pathways and of proteins inhibiting the apoptosis, the inhibition of the cytochrome drug metabolism by other concomitant treatments are some of the recognized patterns of tumor escape. The knowledge of these topics might implement the model of the 'AML umbrella trial' study through the combinations or sequences of new target drugs, preemptively targeting known mechanisms of resistance, with the aim to improve the potential curative rates, expecially in

Target Drugs in Acute Myeloid

*Debora Capelli, Francesco Saraceni, Diego Menotti,* 

*Alessandro Fiorentini and Attilio Olivieri*

elderly patients not eligible to transplant.

**1. Introduction**

**Keywords:** acute myeloid Leukemia, FLT3 inhibitors, IDH inhibitors, BCL2 inhibitors, mechanisms of resistance, immunotherapy, target therapy

The better knowledge of leukemogenesis has led in the last few years to approval of new target drugs for AML treatment. The availability of these drugs has dramatically changed the AML treatment guidelines, supported by the evidence of their efficacy on a molecular driven basis approach. Neverthless primary resistance and clonal evolution leading to adaptive resistance is a recurring theme even in this setting. Actually acute myeloid leukemia (AML) is the result of a multi-step sequence of events resulting in impairment of lineage differentiation, hematopoiesis and enhanced self-renewal. Somatic mutations contribute to AML pathogenesis in different manner. Analysis of healthy population exomic and genomic sequencing [1] showed a correlation between pre-leukemic somatic mutations (IDH1/2, SRSF2, U2AF1, TP53, RUNX1, PPM1D) and subsequent development of AML, as first step
