Induction of acute lymphocytic leukemia differentiation by maintenance therapy

Abstract

Despite extensive study in many malignancies, maintenance therapy has clinically benefited only two diseases: acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL). ALL maintenance therapy utilizes low-dose 6-mercaptopurine (6MP) and methotrexate (MTX), while maintenance in APL primarily consists of all-trans-retinoic acid (ATRA). 6MP and MTX as used in ALL are also now usually added to maintenance ATRA for APL, based on data suggesting an improved disease-free survival. Although the mechanism of action of MTX and 6MP as maintenance is unknown, low-dose cytotoxic agents are potent inducers of differentiation in vitro. Thus, we studied whether maintenance therapy in ALL, like ATRA in APL, may be inducing terminal differentiation of ALL progenitors. The APL cell line NB4, the ALL cell lines REH and RS4;11, and patients' ALL blasts were incubated with ATRA, 6MP, and MTX in vitro. All three drugs inhibited the clonogenic growth of the APL and ALL cell lines without inducing immediate apoptosis, but associated with induction of phenotypic differentiation. The three drugs similarly upregulated lymphoid antigen expression, while decreasing CD34 expression, on patients' ALL blasts. These data suggest that induction of leukemia progenitor differentiation plays an important role in the mechanism of action of maintenance therapy in ALL.

Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia

“…In contrast, bexarotene did not significantly reduce proliferation in mouse BCR-ABL1 leukemic cells lacking Arf/Ikzf1 alterations (Figure S4D). Reduced proliferation and abrogation of clustering was observed in non-BCR-ABL1 human leukemic cells with IKZF1 alterations, including Ph-like ALL cells expressing PAG1-ABL2 or harboring EPOR rearrangements (Figure S4D-E), as has been reported for retinoids in non-BCR-ABL1 ALL cells (Zhang et al, 2002; Lin et al, 2007)…”

A reliable Raman-spectroscopy-based approach for diagnosis, classification and follow-up of B-cell acute lymphoblastic leukemia

“…To provide a scenario as close as possible to the clinical setting, we analyzed these particular RS variations under ‘treatment’ with two clinically demonstrated beneficial drugs that are used in maintenance chemotherapy of patients with B-ALL: MTX and 6MP. Low doses of MTX and 6MP that provide patients with peak plasma concentrations range from 0.01 μM to 1 μM 41 are used to induce specific B-ALL regression. MTX and 6MP are also specific treatments for patients with B-ALL, as they do not provide benefits for other leukemias, such as for regression of acute promyelocytic leukemia, where the maintenance therapy is primarily ATRA 41 .…”

“…In the present study, we demonstrate that RS can be used to identify and classify three B-leukemia cell types that closely mimic the different differentiation/maturation stages of B-ALL cells (i.e., RS4;11, REH, MN60 cells) versus their normal B-cell counterparts. We have also used RS to analyze the biochemical features of these B-leukemia cell lines after low-dose and noncytotoxic treatments with methotrexate (MTX) and 6-mercaptopurine (6MP), the two key drugs used in current B-ALL maintenance therapy 41 .…”

Homeobox protein VentX induces p53-independent apoptosis in cancer cells

“…Current chemo- and radiation therapy focus primarily on disrupting proliferation of cancer cells and are often limited by significant side effects. Though targeting differentiation offers potential novel opportunities in cancer treatment [27], this approach is currently limited by our incomplete understanding of the cellular programs involved in the process.…”