۱- Acute leukemias — Novel therapeutics are urgently required

۲- cAMP-dependent pathway – A meaningful target in hematological malignancies

۳- Targeting cAMP transporters/efflux – an unexplored approach to modulation of the cyclic nucleotide pathway

۴- Conclusions

References

Abstract

While current treatment regimens for acute leukemia can dramatically improve patient survival, there remains room for improvement. Due to its roles in cell differentiation, cell survival, and apoptotic signaling, modulation of the cyclic AMP (cAMP) pathway has provided a meaningful target in hematological malignancies. Several studies have demonstrated that gene expression profiles associated with increased pro-survival cAMP activity or downregulation of various pro-apoptotic factors associated with the cAMP pathway are apparent in acute leukemia patients. Previous work to increase leukemia cell intracellular cAMP focused on the use of cAMP analogs, stimulating cAMP production via transmembrane-associated adenylyl cyclases, or decreasing cAMP degradation by inhibiting phosphodiesterase activity. However, targeting cyclic nucleotide efflux by ATP-binding cassette (ABC) transporters represents an unexplored approach for modulation of intracellular cyclic nucleotide levels. Preliminary studies have shown that inhibition of cAMP efflux can stimulate leukemia cell differentiation, cell growth arrest, and apoptosis, indicating that targeting cAMP efflux may show promise for future therapeutic development. Furthermore, inhibition of cyclic nucleotide transporter activity may also contribute multiple anticancer benefits by reducing extracellular pro-survival signaling in malignant cells. Hence, several opportunities for drug repurposing may exist for targeting cyclic nucleotide transporters.

Biology and etiology of acute leukemias

While not the most prevalent malignancy in the United States, acute leukemia ranks among the top ten cancers in terms of both morbidity and mortality [1]. These hematological malignancies involve aberrant proliferation of blood cells with immature phenotypes. Acute leukemias are typically identified by the presence of > 20% blast cells in the peripheral blood or bone marrow [2]. Due to inherent characteristics related to a reduced differentiation state, and the ability to rapidly propagate, acute leukemias may have worse prognoses than chronic leukemias. Acute myelogenous leukemia (AML) is most prominent in elderly adults over 65 years of age. Annually, 21,450 cases are diagnosed in the United States, and 10,920 cases succumb to the disease [1]. The five year overall survival for this disease is a disheartening 28.3% for adults [1] and about 60% for children [3]. T-cell lineage and B-cell precursor acute lymphoblastic leukemia (T-ALL and B-ALL) primarily affects children, adolescents and young adults, with about 6,000 new cases diagnosed and 1,500 deaths each year [4, 5]. This disease is considered > 80% curable, however there is much room for improvement, specifically for high-risk subtypes such as Ph-like ALL, leukemias harboring rearrangements of KMT2A gene at 11q23 or BCR-ABL1 translocations, etc. [6-8] Therefore, there is a strong need for the development of novel approaches to treat these malignancies and improve patient outcome. The primary classification of acute leukemia is based on the presence of chromosomal abnormalities and translocations along with immunophenotyping. For example, 25-30% of B-ALL have hyperdiploidy [9], while a surprising 40-50% of AML are cytogenetically normal [2]. An analysis of primary AML samples determined an average of 13 mutated genes per sample [10]. It has also been reported that > 80% of B-ALL cases contain deletions within genes related to B cell development [11]. De novo B-ALL genomes also contain 10-20 gene coding mutations [12]. Most commonly, the etiology of acute leukemias is attributed to the combination of mutations that govern pro-survival signaling and reduce tumor suppressor genes [13]. Many factors are potentially implicated in leukemogenesis, and most include aberrancies that increase cell proliferation and induce differential arrest. Due to potential mutations, rapid growth, and deviant signaling, leukemia cells have the capacity to overcome normal mechanisms that would typically result in cell death.