Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs

Abstract

The concept of differentiation therapy of cancer is ~40 years old. Despite many encouraging results obtained in laboratories, both in vitro and in vivo studies, the only really successful clinical application of differentiation therapy was all-trans-retinoic acid (ATRA)-based therapy of acute promyelocytic leukemia (APL). ATRA, which induces granulocytic differentiation of APL leukemic blasts, has revolutionized the therapy of this disease by converting it from a fatal to a curable one. However, ATRA does not work for other acute myeloid leukemias (AMLs). Since 1,25-dihydroxyvitamin D3 (1,25D) is capable of inducing monocytic differentiation of leukemic cells, the idea of treating other AMLs with vitamin D analogs (VDAs) was widely accepted. Also, some types of solid cancers responded to in vitro applied VDAs, and hence it was postulated that VDAs can be used in many clinical applications. However, early clinical trials in which cancer patients were treated either with 1,25D or with VDAs, did not lead to conclusive results. In order to search for a molecular basis of such unpredictable responses of AML patients toward VDAs, we performed ex vivo experiments using patient’s blast cells. Experiments were also performed using 1,25D-responsive and 1,25D-non-responsive cell lines, to study their mechanisms of resistance toward 1,25D-induced differentiation. We found that one of the possible reasons might be due to a very low expression level of vitamin D receptor (VDR) mRNA in resistant cells, which can be increased by exposing the cells to ATRA. Our considerations concerning the molecular mechanism behind the low VDR expression and its regulation by ATRA are reported in this paper.

Oxidative stress, redox regulation and diseases of cellular differentiation

“…Targeted therapy in AML was initially proposed in the late twentieth century by trying to force malignant cells to differentiate. Many cancer subtypes displayed alterations in the normal program of differentiation and growth; thus, the use of specific agents that might trigger differentiation of leukemic cells along normal hematopoietic lineages seemed a logical approach [141, 142]. All- trans retinoic acid (ATRA, also known as Tretinoin) was the first clinically useful cyto-differentiating agent employed in the treatment of acute promyelocytic leukemia (APL, a unique subtype of AML) [143].…”

Up-Regulation of the Vitamin D Pathway in Acute Myeloid Leukemia: A Novel Cause of Hypercalcemia

“…Indeed, previous experiments have demonstrated that vitamin D treatment can induce monocytic differentiation of leukemic precursors [7]. Predicated on these preclinical data and the success of all-trans-retinoic acid differentiation therapy for acute promyelocytic leukemia (APML), non-APML AML cases have also been treated with vitamin D and analogues, but with limited success [8].…”

RNAi-based Gene Therapy for Blood Genetic Diseases

“…APL is the M3 type of acute myeloid leukemia characterized by a clonal proliferation of abnormal promyelocytes in bone marrow and has a severe bleeding tendency. In 98% of APL patients, a balanced translocation between chromosomes 15 and 17 [t(15;17) (q22;q21)] was found, which leads to the formation and fusion of promelocytic leukemia protein (PML) and retinoic acid receptor alpha (RARα) [30,31]. A variety of chromosomal aberrations have been identified in APL including t(11;17)(q23;q21), t(5;17)(q35;q12-21), t(11;17)(q13;q21), and der (17), in which the RARα gene is fused to the PLZF, NPM, NuMA, and STAT5b genes, respectively [32].…”