**Author details**

Javier Marco1,2, Irene Peris2,3, Carmen Vicente1,2,3 and Elena Arriazu1,2,4\*

1 Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain

2 Biochemistry and Genetics Department, University of Navarra, Pamplona, Spain


\*Address all correspondence to: earriazu@unav.es

© 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.

**67**

*The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia*

[11] Low ICC, Loh T, Huang Y, Virshup DM, Pervaiz S. Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity. Blood. 2014 Oct 2;124(14):2223-34.

[12] Perrotti D, Neviani P. Protein phosphatase 2A: a target for anticancer

therapy. Lancet Oncol. 2013

[13] Neviani P, Harb JG, Oaks JJ, Santhanam R, Walker CJ, Ellis JJ, et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest. 2013

[14] Arriazu E, Pippa R, Odero MD. Protein Phosphatase 2A as a Therapeutic Target in Acute Myeloid Leukemia.

[15] Schönthal AH. Role of serine/ threonine protein phosphatase 2A in cancer. Cancer Lett. 2001

[16] Haesen D, Sents W, Lemaire K, Hoorne Y, Janssens V. The Basic Biology of PP2A in Hematologic Cells and Malignancies. Front Oncol. 2014 Dec

[17] Eichhorn PJA, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim

Biophys Acta - Rev Cancer. 2009

[18] Lambrecht C, Haesen D, Sents W, Ivanova E, Janssens V. Structure, Regulation, and Pharmacological Modulation of PP2A Phosphatases. In

[19] Sablina AA, Hector M, Colpaert N, Hahn WC. Identification of PP2A Complexes and Pathways Involved in

May;14(6):e229-38.

Oct 1;123(10):4144-57.

Front Oncol. 2016 Apr 6;6.

Sep;170(1):1-13.

Jan;1795(1):1-15.

2013. p. 283-305.

11;4.

*DOI: http://dx.doi.org/10.5772/intechopen.94380*

[1] DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood. 2020;**135**:85-96

[3] Smith CC. The growing landscape of FLT3 inhibition in AML. Hematology Am Soc Hematol Educ Program.

[4] Antar AI, Otrock ZK, Jabbour E, Mohty M, Bazarbachi A. FLT3 inhibitors

frequently asked questions. Leukemia.

[5] DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020.

[6] Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33:299-312.

[7] Fowle H, Zhao Z, Graña X. PP2A holoenzymes, substrate specificity driving cellular functions and

deregulation incancer. Adv Cancer Res.

[8] Bertolotti A. The split protein phosphatase system. Biochem J.

[9] Mumby M. PP2A: Unveiling a Reluctant Tumor Suppressor. Cell. 2007

[10] Westermarck J, Hahn WC. Multiple pathways regulated by the tumor suppressor PP2A in

transformation. Trends Mol Med. 2008

in acute myeloid leukemia: ten

2020. Published 2020 Jan 9.

Published 2020 Jan 13.

2019;144:55-93

2018;475:3707-3723.

Jul;130(1):21-4.

Apr;14(4):152-60.

[2] Perl AE. Availability of FLT3 inhibitors: how do we use them? Blood.

**References**

2019;134:741-45.

2019;2019:539-47.

*The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94380*

### **References**

*Acute Leukemias*

**Conflict of interest**

**Abbreviations**

**66**

**Author details**

Pamplona, Spain

Javier Marco1,2, Irene Peris2,3, Carmen Vicente1,2,3 and Elena Arriazu1,2,4\*

1 Centro de Investigación Médica Aplicada (CIMA), University of Navarra,

(Co-financed with FEDER funds), Department of Health of the Government of Navarra (29/2015) (M.D.O.), Department of Industry of the Government of

Navarra (0011-1365-2016-000294) (M.D.O.).

The authors declare no conflict of interest.

AML acute myeloid leukemia

CIP2A cancerous inhibitor of PP2A

iHAPs improved heterocyclic activators of PP2A

CML chronic myeloid leukemia

PADs PP2A-activating drugs PP2A protein phosphatase 2A SETBP1 SET binding protein 1 TKI tyrosine kinase inhibitors

BM bone marrow

CK2 casein kinase 2

NK natural killer OA okadiac acid

3 IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

4 CIBERONC, Instituto de Salud Carlos III, Madrid, Spain

\*Address all correspondence to: earriazu@unav.es

provided the original work is properly cited.

2 Biochemistry and Genetics Department, University of Navarra, Pamplona, Spain

© 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,

[1] DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood. 2020;**135**:85-96

[2] Perl AE. Availability of FLT3 inhibitors: how do we use them? Blood. 2019;134:741-45.

[3] Smith CC. The growing landscape of FLT3 inhibition in AML. Hematology Am Soc Hematol Educ Program. 2019;2019:539-47.

[4] Antar AI, Otrock ZK, Jabbour E, Mohty M, Bazarbachi A. FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. Leukemia. 2020. Published 2020 Jan 9.

[5] DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020. Published 2020 Jan 13.

[6] Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33:299-312.

[7] Fowle H, Zhao Z, Graña X. PP2A holoenzymes, substrate specificity driving cellular functions and deregulation incancer. Adv Cancer Res. 2019;144:55-93

[8] Bertolotti A. The split protein phosphatase system. Biochem J. 2018;475:3707-3723.

[9] Mumby M. PP2A: Unveiling a Reluctant Tumor Suppressor. Cell. 2007 Jul;130(1):21-4.

[10] Westermarck J, Hahn WC. Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol Med. 2008 Apr;14(4):152-60.

[11] Low ICC, Loh T, Huang Y, Virshup DM, Pervaiz S. Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity. Blood. 2014 Oct 2;124(14):2223-34.

[12] Perrotti D, Neviani P. Protein phosphatase 2A: a target for anticancer therapy. Lancet Oncol. 2013 May;14(6):e229-38.

[13] Neviani P, Harb JG, Oaks JJ, Santhanam R, Walker CJ, Ellis JJ, et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest. 2013 Oct 1;123(10):4144-57.

[14] Arriazu E, Pippa R, Odero MD. Protein Phosphatase 2A as a Therapeutic Target in Acute Myeloid Leukemia. Front Oncol. 2016 Apr 6;6.

[15] Schönthal AH. Role of serine/ threonine protein phosphatase 2A in cancer. Cancer Lett. 2001 Sep;170(1):1-13.

[16] Haesen D, Sents W, Lemaire K, Hoorne Y, Janssens V. The Basic Biology of PP2A in Hematologic Cells and Malignancies. Front Oncol. 2014 Dec 11;4.

[17] Eichhorn PJA, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta - Rev Cancer. 2009 Jan;1795(1):1-15.

[18] Lambrecht C, Haesen D, Sents W, Ivanova E, Janssens V. Structure, Regulation, and Pharmacological Modulation of PP2A Phosphatases. In 2013. p. 283-305.

[19] Sablina AA, Hector M, Colpaert N, Hahn WC. Identification of PP2A Complexes and Pathways Involved in

Cell Transformation. Cancer Res. 2010 Dec 15;70(24):10474-84.

[20] Janssens V, Longin S, Goris J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci. 2008 Mar;33(3):113-21.

[21] Leulliot N, Quevillon-Cheruel S, Sorel I, de La Sierra-Gallay IL, Collinet B, Graille M, et al. Structure of Protein Phosphatase Methyltransferase 1 (PPM1), a Leucine Carboxyl Methyltransferase Involved in the Regulation of Protein Phosphatase 2A Activity. J Biol Chem. 2004 Feb 27;279(9):8351-8.

[22] Longin S, Zwaenepoel K, Louis J V., Dilworth S, Goris J, Janssens V. Selection of Protein Phosphatase 2A Regulatory Subunits Is Mediated by the C Terminus of the Catalytic Subunit. J Biol Chem. 2007 Sep 14;282(37):26971-80.

[23] Cristóbal I, Garcia-Orti L, Cirauqui C, Alonso MM, Calasanz MJ, Odero MD. PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect. Leukemia. 2011 Apr 14;25(4):606-14.

[24] Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, et al. Protein Kinases and Phosphatases in the Control of Cell Fate. Enzyme Res. 2011;2011:1-26.

[25] Roberts KG, Smith AM, McDougall F, Carpenter H, Horan M, Neviani P, et al. Essential Requirement for PP2A Inhibition by the Oncogenic Receptor c-KIT Suggests PP2A Reactivation as a Strategy to Treat c-KIT + Cancers. Cancer Res. 2010 Jul 1;70(13):5438-47.

[26] Ramaswamy K, Spitzer B, Kentsis A. Therapeutic Re-Activation of Protein Phosphatase 2A in Acute Myeloid Leukemia. Front Oncol. 2015 Feb 2;5.

[27] Agarwal A, MacKenzie RJ, Pippa R, Eide CA, Oddo J, Tyner JW, et al. Antagonism of SET Using OP449 Enhances the Efficacy of Tyrosine Kinase Inhibitors and Overcomes Drug Resistance in Myeloid Leukemia. Clin Cancer Res. 2014 Apr 15;20(8):2092-103.

[28] Vicente C, Arriazu E, Martínez-Balsalobre E, Peris I, Marcotegui N, García-Ramírez P, et al. A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity. Cancer Lett. 2020 Jan;468:1-13.

[29] Cristobal I, Garcia-Orti L, Cirauqui C, Cortes-Lavaud X, Garcia-Sanchez MA, Calasanz MJ, et al. Overexpression of SET is a recurrent event associated with poor outcome and contributes to protein phosphatase 2A inhibition in acute myeloid leukemia. Haematologica. 2012 Apr 1;97(4):543-50.

[30] Pippa R, Dominguez A, Christensen DJ, Moreno-Miralles I, Blanco-Prieto MJ, Vitek MP, et al. Effect of FTY720 on the SET–PP2A complex in acute myeloid leukemia; SET binding drugs have antagonistic activity. Leukemia. 2014 Sep 30;28(9):1915-8.

[31] Barragan E, Chillon MC, Castello-Cros R, Marcotegui N, Prieto MI, Hoyos M, et al. CIP2A high expression is a poor prognostic factor in normal karyotype acute myeloid leukemia. Haematologica. 2015 May 1;100(5):e183-5.

[32] de Mendoza AE-H, Castello-Cros R, Imbuluzqueta E, Cirauqui C, Pippa R, Odero MD, et al. Lipid Nanosystems Enhance the Bioavailability and the Therapeutic Efficacy of FTY720 in Acute Myeloid Leukemia. J Biomed Nanotechnol. 2015 Apr 1;11(4):691-701.

[33] Sangodkar J, Farrington CC, McClinch K, Galsky MD, Kastrinsky DB, Narla G. All roads lead

**69**

*The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia*

[41] Hwang J, Lee JA, Pallas DC. Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes. J Biol Chem. 2016 Sep

[42] Sontag J-M, Nunbhakdi-Craig V,

Djordjevic S. The structure of human leucine carboxyl methyltransferase 1 that regulates protein phosphatase PP2A. Acta Crystallogr Sect D Biol Crystallogr. 2011 Jan 1;67(1):14-24.

[44] Li M, Makkinje A, Damuni Z. The Myeloid Leukemia-associated Protein SET Is a Potent Inhibitor of Protein Phosphatase 2A. J Biol Chem. 1996 May

Sontag E. Leucine Carboxyl Methyltransferase 1 (LCMT1) dependent Methylation Regulates the Association of Protein Phosphatase 2A and Tau Protein with Plasma Membrane Microdomains in Neuroblastoma Cells. J Biol Chem. 2013 Sep 20;288(38):27396-405.

[43] Tsai M-L, Cronin N,

10;271(19):11059-62.

1994;340(3):231-5.

10;111(4):501-7.

[45] Adachr Y, Pavlakis GN, Copeland TD. Identification of in vivo phosphorylation sites of SET, a nuclear phosphoprotein encoded by the translocation breakpoint in acute undifferentiated leukemia. FEBS Lett.

[46] Saito S, Miyaji-Yamaguchi M, Nagata K. Aberrant intracellular

[47] Seo S, McNamara P, Heo S, Turner A, Lane WS, Chakravarti D. Regulation of Histone Acetylation and Transcription by INHAT, a Human Cellular Complex Containing

localization of SET-CAN fusion protein, associated with a leukemia, disorganizes nuclear export. Int J Cancer. 2004 Sep

30;291(40):21008-19.

*DOI: http://dx.doi.org/10.5772/intechopen.94380*

to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J.

[34] Wang SS. Alterations of the PPP2R1B Gene in Human Lung and Colon Cancer. Science (80- ). 1998 Oct

[35] Calin GA, di Iasio MG, Caprini E, Vorechovsky I, Natali PG, Sozzi G, et al. Low frequency of alterations of the α (PPP2R1A) and β (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene. 2000 Feb

[36] Ruediger R, Pham HT, Walter G. Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene. Oncogene. 2001 Apr;20(15):1892-9.

[37] Ruediger R, Pham HT, Walter G. Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene. Oncogene. 2001 Apr;20(15):1892-9.

[38] Esplin ED, Ramos P, Martinez B, Tomlinson GE, Mumby MC, Evans GA. The glycine 90 to aspartate alteration in the Aβ subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. Genes, Chromosom Cancer. 2006

[39] Kalla C, Scheuermann MO, Kube I, Schlotter M, Mertens D, Döhner H, et al. Analysis of 11q22–q23 deletion target genes in B-cell chronic lymphocytic leukaemia: Evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B. Eur J

Cancer. 2007 May;43(8):1328-35.

[40] Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013

May 30;368(22):2059-74.

Feb;45(2):182-90.

2016 Mar;283(6):1004-24.

9;282(5387):284-7.

7;19(9):1191-5.

*The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94380*

to PP2A: exploiting the therapeutic potential of this phosphatase. FEBS J. 2016 Mar;283(6):1004-24.

*Acute Leukemias*

Dec 15;70(24):10474-84.

[20] Janssens V, Longin S,

Mar;33(3):113-21.

27;279(9):8351-8.

Cell Transformation. Cancer Res. 2010

[27] Agarwal A, MacKenzie RJ, Pippa R, Eide CA, Oddo J, Tyner JW, et al. Antagonism of SET Using OP449 Enhances the Efficacy of Tyrosine Kinase Inhibitors and Overcomes Drug Resistance in Myeloid Leukemia. Clin Cancer Res. 2014 Apr 15;20(8):2092-103.

[28] Vicente C, Arriazu E, Martínez-Balsalobre E, Peris I,

2020 Jan;468:1-13.

Apr 1;97(4):543-50.

[30] Pippa R, Dominguez A, Christensen DJ, Moreno-Miralles I, Blanco-Prieto MJ, Vitek MP, et al. Effect of FTY720 on the SET–PP2A complex in acute myeloid leukemia; SET binding

drugs have antagonistic activity. Leukemia. 2014 Sep 30;28(9):1915-8.

Castello-Cros R, Marcotegui N, Prieto MI, Hoyos M, et al. CIP2A high expression

[32] de Mendoza AE-H, Castello-Cros R, Imbuluzqueta E, Cirauqui C, Pippa R, Odero MD, et al. Lipid Nanosystems Enhance the Bioavailability and the Therapeutic Efficacy of FTY720 in Acute Myeloid Leukemia. J Biomed Nanotechnol. 2015 Apr 1;11(4):691-701.

[33] Sangodkar J, Farrington CC, McClinch K, Galsky MD,

Kastrinsky DB, Narla G. All roads lead

[31] Barragan E, Chillon MC,

is a poor prognostic factor in normal karyotype acute myeloid leukemia. Haematologica. 2015 May

1;100(5):e183-5.

Marcotegui N, García-Ramírez P, et al. A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity. Cancer Lett.

[29] Cristobal I, Garcia-Orti L, Cirauqui C, Cortes-Lavaud X, Garcia-Sanchez MA, Calasanz MJ, et al. Overexpression of SET is a recurrent event associated with poor outcome and contributes to protein phosphatase 2A inhibition in acute myeloid leukemia. Haematologica. 2012

Goris J. PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem Sci. 2008

[21] Leulliot N, Quevillon-Cheruel S, Sorel I, de La Sierra-Gallay IL,

1 (PPM1), a Leucine Carboxyl Methyltransferase Involved in the Regulation of Protein Phosphatase 2A Activity. J Biol Chem. 2004 Feb

2007 Sep 14;282(37):26971-80.

[23] Cristóbal I, Garcia-Orti L,

[24] Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, et al. Protein Kinases and Phosphatases in the Control of Cell Fate.

Enzyme Res. 2011;2011:1-26.

[25] Roberts KG, Smith AM,

1;70(13):5438-47.

McDougall F, Carpenter H, Horan M, Neviani P, et al. Essential Requirement for PP2A Inhibition by the Oncogenic Receptor c-KIT Suggests PP2A Reactivation as a Strategy to Treat c-KIT + Cancers. Cancer Res. 2010 Jul

[26] Ramaswamy K, Spitzer B, Kentsis A. Therapeutic Re-Activation of Protein Phosphatase 2A in Acute Myeloid Leukemia. Front Oncol. 2015 Feb 2;5.

Cirauqui C, Alonso MM, Calasanz MJ, Odero MD. PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect. Leukemia. 2011 Apr 14;25(4):606-14.

Collinet B, Graille M, et al. Structure of Protein Phosphatase Methyltransferase

[22] Longin S, Zwaenepoel K, Louis J V., Dilworth S, Goris J, Janssens V. Selection of Protein Phosphatase 2A Regulatory Subunits Is Mediated by the C Terminus of the Catalytic Subunit. J Biol Chem.

**68**

[34] Wang SS. Alterations of the PPP2R1B Gene in Human Lung and Colon Cancer. Science (80- ). 1998 Oct 9;282(5387):284-7.

[35] Calin GA, di Iasio MG, Caprini E, Vorechovsky I, Natali PG, Sozzi G, et al. Low frequency of alterations of the α (PPP2R1A) and β (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms. Oncogene. 2000 Feb 7;19(9):1191-5.

[36] Ruediger R, Pham HT, Walter G. Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene. Oncogene. 2001 Apr;20(15):1892-9.

[37] Ruediger R, Pham HT, Walter G. Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene. Oncogene. 2001 Apr;20(15):1892-9.

[38] Esplin ED, Ramos P, Martinez B, Tomlinson GE, Mumby MC, Evans GA. The glycine 90 to aspartate alteration in the Aβ subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function. Genes, Chromosom Cancer. 2006 Feb;45(2):182-90.

[39] Kalla C, Scheuermann MO, Kube I, Schlotter M, Mertens D, Döhner H, et al. Analysis of 11q22–q23 deletion target genes in B-cell chronic lymphocytic leukaemia: Evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B. Eur J Cancer. 2007 May;43(8):1328-35.

[40] Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013 May 30;368(22):2059-74.

[41] Hwang J, Lee JA, Pallas DC. Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes. J Biol Chem. 2016 Sep 30;291(40):21008-19.

[42] Sontag J-M, Nunbhakdi-Craig V, Sontag E. Leucine Carboxyl Methyltransferase 1 (LCMT1) dependent Methylation Regulates the Association of Protein Phosphatase 2A and Tau Protein with Plasma Membrane Microdomains in Neuroblastoma Cells. J Biol Chem. 2013 Sep 20;288(38):27396-405.

[43] Tsai M-L, Cronin N, Djordjevic S. The structure of human leucine carboxyl methyltransferase 1 that regulates protein phosphatase PP2A. Acta Crystallogr Sect D Biol Crystallogr. 2011 Jan 1;67(1):14-24.

[44] Li M, Makkinje A, Damuni Z. The Myeloid Leukemia-associated Protein SET Is a Potent Inhibitor of Protein Phosphatase 2A. J Biol Chem. 1996 May 10;271(19):11059-62.

[45] Adachr Y, Pavlakis GN, Copeland TD. Identification of in vivo phosphorylation sites of SET, a nuclear phosphoprotein encoded by the translocation breakpoint in acute undifferentiated leukemia. FEBS Lett. 1994;340(3):231-5.

[46] Saito S, Miyaji-Yamaguchi M, Nagata K. Aberrant intracellular localization of SET-CAN fusion protein, associated with a leukemia, disorganizes nuclear export. Int J Cancer. 2004 Sep 10;111(4):501-7.

[47] Seo S, McNamara P, Heo S, Turner A, Lane WS, Chakravarti D. Regulation of Histone Acetylation and Transcription by INHAT, a Human Cellular Complex Containing the Set Oncoprotein. Cell. 2001 Jan;104(1):119-30.

[48] Kutney SN, Hong R, Macfarlan T, Chakravarti D. A Signaling Role of Histone-binding Proteins and INHAT Subunits pp32 and Set/TAF-Iβ in Integrating Chromatin Hypoacetylation and Transcriptional Repression. J Biol Chem. 2004 Jul 16;279(29):30850-5.

[49] Kalousi A, Hoffbeck A-S, Selemenakis PN, Pinder J, Savage KI, Khanna KK, et al. The Nuclear Oncogene SET Controls DNA Repair by KAP1 and HP1 Retention to Chromatin. Cell Rep. 2015 Apr;11(1):149-63.

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[73] Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, et al. CIP2A Is Associated with Human Breast Cancer Aggressivity. Clin Cancer Res. 2009 Aug

[74] Khanna A, Böckelman C,

Hemmes A, Junttila MR, Wiksten J-P, Lundin M, et al. MYC-Dependent Regulation and Prognostic Role of CIP2A in Gastric Cancer. JNCI J Natl Cancer Inst. 2009

[75] Dong Q-Z, Wang Y, Dong X-J, Li Z-X, Tang Z-P, Cui Q-Z, et al. CIP2A is Overexpressed in Non-Small Cell Lung Cancer and Correlates with Poor Prognosis. Ann Surg Oncol. 2011 Mar

Zou X, Zhang G, Xiao R, et al. CIP2A is a predictor of survival and a novel therapeutic target in bladder urothelial cell carcinoma. Med Oncol. 2013 Mar

15;15(16):5092-100.

Jun;101(11):793-805.

15;18(3):857-65.

30;30(1):406.

[76] Xue Y, Wu G, Wang X,

Jul;130(1):51-62.

*DOI: http://dx.doi.org/10.5772/intechopen.94380*

Nebreda AR. Genetic analysis of specific and redundant roles for p38 and p38 MAPKs during mouse development. Proc Natl Acad Sci. 2011 Aug

[63] Grethe S, Pörn-Ares MI. p38 MAPK regulates phosphorylation of Bad via PP2A-dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-α induced endothelial apoptosis. Cell Signal. 2006 Apr;18(4):531-40.

[64] Junttila MR, Li S, Westermarck J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J.

[66] Guillonneau M, Paris F, Dutoit S, Estephan H, Bénéteau E, Huot J, et al. Oxidative stress disassembles the p38/ NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response. FASEB J. 2016 Aug 3;30(8):2899-914.

[67] Trotta R, Ciarlariello D, Col JD, Allard J, Neviani P, Santhanam R, et al. The PP2A inhibitor SET regulates natural killer cell IFN-γ production. J Exp Med. 2007 Oct 1;204(10):2397-405.

[68] Trotta R, Ciarlariello D, Dal Col J, Mao H, Chen L, Briercheck E, et al. The PP2A inhibitor SET regulates granzyme B expression in human natural killer cells. Blood. 2011 Feb 24;117(8):2378-84.

[69] Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, et al. CIP2A Inhibits PP2A

2008 Apr 26;22(4):954-65.

Nov 20;7(11):e49605.

[65] Lin S-P, Lee Y-T, Wang J-Y, Miller SA, Chiou S-H, Hung M-C, et al. Survival of Cancer Stem Cells under Hypoxia and Serum Depletion via Decrease in PP2A Activity and Activation of p38-MAPKAPK2-Hsp27. Koritzinsky M, editor. PLoS One. 2012

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2;108(31):12764-9.

*The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94380*

[62] del Barco Barrantes I, Coya JM, Maina F, Arthur JSC, Nebreda AR. Genetic analysis of specific and redundant roles for p38 and p38 MAPKs during mouse development. Proc Natl Acad Sci. 2011 Aug 2;108(31):12764-9.

*Acute Leukemias*

Jan;104(1):119-30.

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2005 Nov;8(5):355-68.

1;120(7):2254-64.

Jan 8;10(1):3.

21;115(3):615-25.

1;75(19):3997-4002.

Jul 29;10(7):1285-300.

22;289(34):23546-56.

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García-Ramírez P, et al. A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia. Blood Cancer J. 2020

**70**

[63] Grethe S, Pörn-Ares MI. p38 MAPK regulates phosphorylation of Bad via PP2A-dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-α induced endothelial apoptosis. Cell Signal. 2006 Apr;18(4):531-40.

[64] Junttila MR, Li S, Westermarck J. Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J. 2008 Apr 26;22(4):954-65.

[65] Lin S-P, Lee Y-T, Wang J-Y, Miller SA, Chiou S-H, Hung M-C, et al. Survival of Cancer Stem Cells under Hypoxia and Serum Depletion via Decrease in PP2A Activity and Activation of p38-MAPKAPK2-Hsp27. Koritzinsky M, editor. PLoS One. 2012 Nov 20;7(11):e49605.

[66] Guillonneau M, Paris F, Dutoit S, Estephan H, Bénéteau E, Huot J, et al. Oxidative stress disassembles the p38/ NPM/PP2A complex, which leads to modulation of nucleophosmin-mediated signaling to DNA damage response. FASEB J. 2016 Aug 3;30(8):2899-914.

[67] Trotta R, Ciarlariello D, Col JD, Allard J, Neviani P, Santhanam R, et al. The PP2A inhibitor SET regulates natural killer cell IFN-γ production. J Exp Med. 2007 Oct 1;204(10):2397-405.

[68] Trotta R, Ciarlariello D, Dal Col J, Mao H, Chen L, Briercheck E, et al. The PP2A inhibitor SET regulates granzyme B expression in human natural killer cells. Blood. 2011 Feb 24;117(8):2378-84.

[69] Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, et al. CIP2A Inhibits PP2A in Human Malignancies. Cell. 2007 Jul;130(1):51-62.

[70] Niemelä M, Kauko O, Sihto H, Mpindi J-P, Nicorici D, Pernilä P, et al. CIP2A signature reveals the MYC dependency of CIP2A-regulated phenotypes and its clinical association with breast cancer subtypes. Oncogene. 2012 Sep 16;31(39):4266-78.

[71] Khanna A, Pimanda JE, Westermarck J. Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target. Cancer Res. 2013 Nov 15;73(22):6548-53.

[72] Luo H, Li Q, O'Neal J, Kreisel F, Le Beau MM, Tomasson MH. c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphomaassociated antiapoptotic mutations. Blood. 2005 Oct 1;106(7):2452-61.

[73] Come C, Laine A, Chanrion M, Edgren H, Mattila E, Liu X, et al. CIP2A Is Associated with Human Breast Cancer Aggressivity. Clin Cancer Res. 2009 Aug 15;15(16):5092-100.

[74] Khanna A, Böckelman C, Hemmes A, Junttila MR, Wiksten J-P, Lundin M, et al. MYC-Dependent Regulation and Prognostic Role of CIP2A in Gastric Cancer. JNCI J Natl Cancer Inst. 2009 Jun;101(11):793-805.

[75] Dong Q-Z, Wang Y, Dong X-J, Li Z-X, Tang Z-P, Cui Q-Z, et al. CIP2A is Overexpressed in Non-Small Cell Lung Cancer and Correlates with Poor Prognosis. Ann Surg Oncol. 2011 Mar 15;18(3):857-65.

[76] Xue Y, Wu G, Wang X,

Zou X, Zhang G, Xiao R, et al. CIP2A is a predictor of survival and a novel therapeutic target in bladder urothelial cell carcinoma. Med Oncol. 2013 Mar 30;30(1):406.

[77] WANG J, LI W, LI L, YU X, JIA J, CHEN C. CIP2A is over-expressed in acute myeloid leukaemia and associated with HL60 cells proliferation and differentiation. Int J Lab Hematol. 2011 Jun;33(3):290-8.

[78] Lucas CM, Harris RJ, Giannoudis A, Copland M, Slupsky JR, Clark RE. Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood. 2011 Jun 16;117(24):6660-8.

[79] Lucas CM, Harris RJ, Holcroft AK, Scott LJ, Carmell N, McDonald E, et al. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients. Leukemia. 2015 Jul 13;29(7):1514-23.

[80] Ciccone M, Calin GA, Perrotti D. From the Biology of PP2A to the PADs for Therapy of Hematologic Malignancies. Front Oncol. 2015 Feb 16;5.

[81] Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, et al. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. N Engl J Med. 2010 Feb 4;362(5):402-15.

[82] Martin R. Anti-CD25 (daclizumab) monoclonal antibody therapy in relapsing–remitting multiple sclerosis. Clin Immunol. 2012 Jan;142(1):9-14.

[83] Oaks JJ, Santhanam R, Walker CJ, Roof S, Harb JG, Ferenchak G, et al. Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies. Blood. 2013 Sep 12;122(11):1923-34.

[84] Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous

leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia. J Clin Invest. 2007 Sep 4;117(9):2408-21.

[85] Arnaud L, Chen S, Liu F, Li B, Khatoon S, Grundke-Iqbal I, et al. Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I 2 PP2A /SET. FEBS Lett. 2011 Sep 2;585(17):2653-9.

[86] Chen L, Luo L-F, Lu J, Li L, Liu Y-F, Wang J, et al. FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels. Siskind LJ, editor. PLoS One. 2014 Jul 22;9(7):e103033.

[87] Christensen DJ, Chen Y, Oddo J, Matta KM, Neil J, Davis ED, et al. SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target. Blood. 2011 Oct 13;118(15):4150-8.

[88] Switzer CH, Cheng RYS, Vitek TM, Christensen DJ, Wink DA, Vitek MP. Targeting SET/I2PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. Oncogene. 2011 Jun 7;30(22):2504-13.

[89] Wlodarchak N, Guo F, Satyshur KA, Jiang L, Jeffrey PD, Sun T, et al. Structure of the Ca2+−dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation. Cell Res. 2013 Jul 11;23(7):931-46.

[90] Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, et al. Structure of the Protein Phosphatase 2A Holoenzyme. Cell. 2006 Dec;127(6):1239-51.

[91] Xu Y, Chen Y, Zhang P, Jeffrey PD, Shi Y. Structure of a Protein Phosphatase 2A Holoenzyme: Insights into

**73**

e20.

*The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia*

*DOI: http://dx.doi.org/10.5772/intechopen.94380*

B55-Mediated Tau Dephosphorylation. Mol Cell. 2008 Sep;31(6):873-85.

[93] Letourneux C, Rocher G, Porteu F. B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J.

[92] Arnold HK, Sears RC. A tumor suppressor role for PP2A-B56α through negative regulation of c-Myc and other key oncoproteins. Cancer Metastasis

Rev. 2008 Jun 2;27(2):147-58.

2006 Feb 22;25(4):727-38.

26;6(268):rs6-rs6.

e16.

[94] Casado P, Rodriguez-Prados J-C, Cosulich SC, Guichard S,

Vanhaesebroeck B, Joel S, et al. Kinase-Substrate Enrichment Analysis Provides Insights into the Heterogeneity of Signaling Pathway Activation in Leukemia Cells. Sci Signal. 2013 Mar

[95] Leonard D, Huang W, Izadmehr S, O'Connor CM, Wiredja DD, Wang Z, et al. Selective PP2A Enhancement through Biased Heterotrimer

Stabilization. Cell. 2020;181(3):688-701.

[97] Morita K, He S, Nowak RP, Wang J, Zimmerman MW, Fu C, et al. Allosteric Activators of Protein Phosphatase 2A Display Broad Antitumor Activity Mediated by Dephosphorylation of MYBL2. Cell. 2020 Apr;181(3):702-715.

[96] Kauko O, O'Connor CM, Kulesskiy E, Sangodkar J, Aakula A, Izadmehr S, et al. PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. Sci Transl Med. 2018 Jul

18;10(450):eaaq1093.

*The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94380*

B55-Mediated Tau Dephosphorylation. Mol Cell. 2008 Sep;31(6):873-85.

*Acute Leukemias*

Jun;33(3):290-8.

16;117(24):6660-8.

13;29(7):1514-23.

4;362(5):402-15.

[83] Oaks JJ, Santhanam R,

16;5.

[80] Ciccone M, Calin GA,

[77] WANG J, LI W, LI L, YU X, JIA J, CHEN C. CIP2A is over-expressed in acute myeloid leukaemia and associated with HL60 cells proliferation and differentiation. Int J Lab Hematol. 2011

leukemia and Philadelphia chromosome–positive acute

2007 Sep 4;117(9):2408-21.

[85] Arnaud L, Chen S, Liu F,

Mechanism of inhibition of PP2A activity and abnormal hyperphosphorylation of tau by I 2 PP2A /SET. FEBS Lett. 2011 Sep

2;585(17):2653-9.

lymphocytic leukemia. J Clin Invest.

Li B, Khatoon S, Grundke-Iqbal I, et al.

[86] Chen L, Luo L-F, Lu J, Li L, Liu Y-F, Wang J, et al. FTY720 Induces Apoptosis of M2 Subtype Acute Myeloid Leukemia Cells by Targeting

[87] Christensen DJ, Chen Y, Oddo J, Matta KM, Neil J, Davis ED, et al. SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target. Blood. 2011 Oct

[88] Switzer CH, Cheng RYS, Vitek TM, Christensen DJ, Wink DA, Vitek MP. Targeting SET/I2PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. Oncogene. 2011 Jun

Satyshur KA, Jiang L, Jeffrey PD, Sun T, et al. Structure of the Ca2+−dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation. Cell Res. 2013

[90] Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, et al. Structure of the Protein Phosphatase 2A Holoenzyme. Cell. 2006

[91] Xu Y, Chen Y, Zhang P, Jeffrey PD, Shi Y. Structure of a Protein Phosphatase

2A Holoenzyme: Insights into

Sphingolipid Metabolism and Increasing Endogenous Ceramide Levels. Siskind LJ, editor. PLoS One.

2014 Jul 22;9(7):e103033.

13;118(15):4150-8.

7;30(22):2504-13.

Jul 11;23(7):931-46.

Dec;127(6):1239-51.

[89] Wlodarchak N, Guo F,

[78] Lucas CM, Harris RJ, Giannoudis A, Copland M, Slupsky JR, Clark RE. Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression. Blood. 2011 Jun

[79] Lucas CM, Harris RJ, Holcroft AK, Scott LJ, Carmell N, McDonald E, et al. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients. Leukemia. 2015 Jul

Perrotti D. From the Biology of PP2A to the PADs for Therapy of Hematologic Malignancies. Front Oncol. 2015 Feb

[81] Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO, Montalban X, et al. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. N Engl J Med. 2010 Feb

[82] Martin R. Anti-CD25 (daclizumab) monoclonal antibody therapy in relapsing–remitting multiple sclerosis. Clin Immunol. 2012 Jan;142(1):9-14.

Walker CJ, Roof S, Harb JG, Ferenchak G, et al. Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod, Gilenya) in Jak2-driven hematologic malignancies. Blood. 2013 Sep 12;122(11):1923-34.

[84] Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous

**72**

[92] Arnold HK, Sears RC. A tumor suppressor role for PP2A-B56α through negative regulation of c-Myc and other key oncoproteins. Cancer Metastasis Rev. 2008 Jun 2;27(2):147-58.

[93] Letourneux C, Rocher G, Porteu F. B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J. 2006 Feb 22;25(4):727-38.

[94] Casado P, Rodriguez-Prados J-C, Cosulich SC, Guichard S, Vanhaesebroeck B, Joel S, et al. Kinase-Substrate Enrichment Analysis Provides Insights into the Heterogeneity of Signaling Pathway Activation in Leukemia Cells. Sci Signal. 2013 Mar 26;6(268):rs6-rs6.

[95] Leonard D, Huang W, Izadmehr S, O'Connor CM, Wiredja DD, Wang Z, et al. Selective PP2A Enhancement through Biased Heterotrimer Stabilization. Cell. 2020;181(3):688-701. e16.

[96] Kauko O, O'Connor CM, Kulesskiy E, Sangodkar J, Aakula A, Izadmehr S, et al. PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells. Sci Transl Med. 2018 Jul 18;10(450):eaaq1093.

[97] Morita K, He S, Nowak RP, Wang J, Zimmerman MW, Fu C, et al. Allosteric Activators of Protein Phosphatase 2A Display Broad Antitumor Activity Mediated by Dephosphorylation of MYBL2. Cell. 2020 Apr;181(3):702-715. e20.

**75**

**Chapter 5**

Melanin, from an Evolutionary

Cell's Main Energy Source. The

Remnant to the Myeloid Lineage

Unsuspected Intrinsic Property of

Melanin to Dissociate the Molecule

from Water. Possible Implications

in the Context of Acute Leukemias

Melanin is one of the most stable substances known. The study of the ink bags of fossilized squid that died 160 million years ago has found it in good condition. Its extraordinary stability is what had prevented, to date; assign a relevant role in biology. Sir Everard Holmes' proposal in London; in the eighteenth century, about the role of melanin as a simple sunscreen, it has permeated to this day, especially among dermatologists. Despite the unique physical–chemical qualities of melanin, its biological role as a simple sunscreen that protects us from the dangerous UV rays remained immutable. Our circumstantial discovery during an observational study that lasted 12 years (1990–2002) and which included the ophthalmologic studies of 6000 patients, about the relationship between the vessels of the optic nerve and the three main causes of blindness (Macular degeneration, diabetes, and glaucoma) allowed us to discern the unexpected and surprising true role of melanin in Biology as an energy transducer. The unsuspected intrinsic property of melanin to transform light into chemical energy through water dissociation, like chlorophyll in plants; opens a new era in Biology and therefore in Medicine. And Acute Leukemias

**Keywords:** energy, mitochondria, melanin, water, hydrogen, oxygen, ATP

Wasserman described the accidental discovery of lymphocytes containing melanin granules in humans since 1963 [1]. Through the reaction to a non-immune Antigen (Egg white), Wasserman found in all the 46 non-White subjects' investigation of the hourly preparations revealed that melanin became discernible in

*Arturo Solís Herrera, Ruth I. Solís Arias* 

*and Luis F. Torres Solís*

**Abstract**

are no exception.

**1. Introduction**
