<p>Targeting of the Alox12-12-HETE in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem/Progenitor Cell Function</p>

Abstract

Introduction: Chronic myeloid leukemia (CML) is a myeloid malignancy characterized by the oncogene BCR-ABL. CML responds well to therapy targeting BCR-ABL in the chronic phase but is resistant to treatment when it progresses to the blast phase (BP). This study attempted to address whether arachidonate 12-lipoxygenase (Alox12) confers to CML drug resistance. Materials and Methods: We analyzed the expression of Alox12 using Western blotting, ELISA, and RT-PCR methods. Loss of functional analysis was performed using cellular activity assays on CML and normal hematopoietic stem/progenitor cells (HSPCs). Results: Alox12 and 12-Hydroxyeicosatetraenoic acid (12-HETE) are overexpressed in BP-CML but not HSPCs, and that Alox12-12-HETE axis is regulated by BCR-ABL. The Alox12-12-HETE axis is required for CML. Specific Alox12 inhibitor inhibits colony formation, survival, and self-renewal capacity in BP-CML HSPCs, and to a significantly greater extent than in normal HSPCs. Of note, the Alox12 inhibitor significantly augments dasatinib's efficacy in BP-CML HSPCs. Mechanism studies show that Alox12 inhibition does not affect activities of essential signaling pathways involved in maintaining stem cell function, such as Wnt, p53, and bone morphogenetic protein (BMP). In contrast, we show that Alox12 inhibition disrupts nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis and induces oxidative stress and damage in CML HSPCs and committed cells. Conclusion: Alox12-12-HETE axis is a specific and critical regulator of BP-CML HSPCs functions. Pharmacological inhibition of Alox12 may be useful in BP-CML.

Disturbed Plasma Lipidomic Profiles in Females with Diffuse Large B-Cell Lymphoma: A Pilot Study

“…The most prominent alterations were those of 12(S)-HETE (3.15-fold) (Table 3), probably reflecting an augmented rate of arachidonate 12-LOX (12-LOX) activity. Considering the overexpression of 12-LOX and its product 12(S)-HETE in one haematological tumour, chronic myeloid leukaemia [75], the prominent rise in plasma content of 12(S)-HETE seen in DLBCL female patients (Table 3) did not surprise us. Enzyme 12-LOX (also known as platelet-type ALOX 12) is coded by ALOX12 located on the chromosome 17p, along with all other genes encoding LOXs, i.e., ALOX15B, ALOX15, ALOX12B and ALOXE3, the only exception being 5-LOX.…”

Understanding and Monitoring Chronic Myeloid Leukemia Blast Crisis: How to Better Manage Patients

“…The disease is caused by the BCR-ABL fusion gene generated from the t (9;22)(q34;q11) reciprocal translocation, encoding the BCR-ABL oncoprotein, which constitutively activates ABL kinase and drives hematopoietic cell proliferation and leukemic transformation. [1][2][3][4][5][6] CML is a natural triphasic course disease starting with the indolent CP, which is characterized by a remarkable increase in myeloid precursors and mature cells and lasts approximately 3-5 years. 7 Without therapeutic intervention, after a median interval of 3-18 months, the disease spontaneously progresses to AP and eventually to highly aggressive BP, characterized by a rapid expansion of primitive cells in the bone marrow that spill into circulation, 8,9 similar to acute leukemia.…”