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

*Javier Marco, Irene Peris, Carmen Vicente and Elena Arriazu*

## **Abstract**

Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of hematopoietic progenitor cells characterized by the accumulation of several genetic and epigenetic mutations. Despite the progressive understanding of the molecular heterogeneity of the disease, the survival rate of patients older than 60 years old remains poor. Therefore, it is necessary to develop an effective treatment strategy for those patients in order to beat the disease and improve life quality. Reversible phosphorylation has been widely studied over the last years, and the deregulation of kinases and phosphatase have been verified to have a huge impact in leukemogenesis. Inactivation of the tumor-suppressor protein phosphatase 2A (PP2A) is frequent in AML patients, constituting a promising target for cancer therapy. There are several PP2A inactivation mechanisms. However, overexpression of SET or cancerous inhibitors of PP2A, both endogenous inhibitors of PP2A, are recurrent events in AML patients, leading to the inactivation of the phosphatase PP2A. Preclinical studies show that PP2A reactivation using PP2A-activating drugs (PADs) manage to stop the development of the disease, and its combination with conventional chemotherapy and tyrosine kinase inhibitors have a synergistic cytotoxic effects. Recent studies have demonstrated that specifically activation of PP2A subunits, target crucial pathogenic drivers, increasing the efficacy of conventional treatments and opening new possibilities for personalized treatment in AML patients, especially in cases of PP2A deregulation. Here, we review the role of PP2A in AML as well as its drugable options.

**Keywords:** AML, PP2A, SET, PADs, FTY720, CM-1231

#### **1. Introduction**

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by the accumulation of poorly differentiated cells, derived from the differentiation blockage of myeloid hematopoietic progenitors in the bone marrow (BM) [1]. As consequence, immature cells called "blast" displace other cell populations invading the BM and other tissues [2, 3].

AML is a malignant disorder of the bone marrow characterized by the clonal expansion and differentiation arrest of myeloid progenitor cells. Incidence increases with age, with 68 years being the median age at diagnosis. AML is the most common form of acute leukemia in adults and has the shortest survival. Effective therapies, including intensive chemotherapy and allogeneic stem cell transplantation, are

generally applicable to young patients, while treatment options for older patients (≥65 years), which are the largest group, have historically been limited to DNA methyltransferase inhibitors (i.e. azacitidine and decitabine) and low doses of cytarabine, and have only provided a modest benefit [1, 4, 5]. Besides, treatment is often ineffective in both groups due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD), that represent ~25% of all AML cases, and have poor outcome, with high risk of relapse and low cure rates [1–6]. The AML treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including midostaurin and gilteritinib to target FLT3, and venetoclax to target BCL-2 [1]. This has created novel treatment options, especially in older as well as in refractory/relapsed patients. The natural history of FLT3-mutated AML is changing after the approval of midostaurin for frontline therapy and gilteritinib for relapsed or refractory patients. Nevertheless, despite initial clinical responses to FLT3 kinase inhibitors (FKIs), patients eventually relapse. Mechanisms of resistance include the acquisition of secondary FLT3 mutations and protective stromal signaling within the bone marrow niche [2–4]. In the same way, venetoclax combined with hypomethylating agents or low-dose cytarabine is an effective therapy for older or unfit patients with AML, which represents most of the cases. However, it is now clear that multiple resistant sub-clones evolving contemporaneously during therapy can occur in AML and act as a barrier to the long-term success of targeted therapies. Studies about the molecular determinants of outcome with clinical relevance to patients with AML show that FLT3-ITD mutations or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies [5]. Besides, even with these and other potent targeted therapies, the disease persists within the bone marrow microenvironment, mainly due to activating parallel signaling pathways that maintain pro-survival factors. Therefore, acquired resistance to these targeted drugs remains a challenge and provides a rationale for combining either FLT3 inhibitors or venetoclax with other therapies, both conventional and investigational [6]. Reversible phosphorylation of proteins is a post-translational modification that regulates all aspect of life through the antagonistic action of kinases and phosphatases. Protein kinases are popular drug targets and are well characterized, but protein phosphatases have been relatively neglected [7]. In this chapter, we will focus on the role of protein phosphatase 2A (PP2A), inactivation of which is a recurrent event in AML, as a druggable tumor suppressor.
