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Role of Vitamins A and D in BCR-ABL Arf-/- Acute Lymphoblastic Leukemia.

ABSTRACT: The effects of vitamin A and/or vitamin D deficiency were studied in an Arf-/- BCR-ABL acute lymphoblastic leukemia murine model. Vitamin D sufficient mice died earlier (p?=?0.003) compared to vitamin D deficient (VDD) mice. Vitamin A deficient (VAD) mice fared worst with more rapid disease progression and decreased survival. Mice deficient for vitamins A and D (VADD) had disease progression similar to VAD mice. Regulatory T cells, previously shown to associate with poor BCR-ABL leukemia control, were present at higher frequencies among CD4+?splenocytes of vitamin A deficient vs. sufficient mice. In vitro studies demonstrated 1,25-dihydroxyvitamin D (1,25(OH)2VD3) increased the number of BCR-ABL ALL cells only when co-cultured with bone marrow stroma. 1,25(OH)2VD3 induced CXCL12 expression in vivo and in vitro in stromal cells and CXCL12 increased stromal migration and the number of BCR-ABL blasts. Vitamin D plus leukemia reprogrammed the marrow increasing production of collagens, potentially trapping ALL blasts. Vitamin A (all trans retinoic acid, ATRA) treated leukemic cells had increased apoptosis, decreased cells in S-phase, and increased cells in G0/G1. ATRA signaled through the retinoid X receptor to decrease BCR-ABL leukemic cell viability. In conclusion, vitamin A and D deficiencies have opposing effects on mouse survival from BCR-ABL ALL.

SUBMITTER: Annu K

PROVIDER: S-EPMC7012907 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Role of Vitamins A and D in BCR-ABL Arf<sup>-/-</sup> Acute Lymphoblastic Leukemia.

Annu Kavya K Cline Cynthia C Yasuda Kazuto K Ganguly Samit S Pesch Andrea A Cooper Brittany B Janke Laura L Payton Monique M Mukherjee Kamalika K Surman Sherri L SL Hurwitz Julia L JL Schuetz Erin G EG

Scientific reports 20200211 1

The effects of vitamin A and/or vitamin D deficiency were studied in an Arf<sup>-/-</sup> BCR-ABL acute lymphoblastic leukemia murine model. Vitamin D sufficient mice died earlier (p = 0.003) compared to vitamin D deficient (VDD) mice. Vitamin A deficient (VAD) mice fared worst with more rapid disease progression and decreased survival. Mice deficient for vitamins A and D (VADD) had disease progression similar to VAD mice. Regulatory T cells, previously shown to associate with poor BCR-ABL leuke ...[more]

PMID: 32047189

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Project description:BackgroundThe Philadelphia chromosome encodes the BCR-ABL fusion protein, which has two primary subtypes, P210 and P190. P210 and P190 cause Philadelphia-positive chronic myeloid leukemia (Ph+ CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL), respectively. The Ph+ ALL is more malignant than Ph+ CML in disease phenotype and progression. This implies the key pathogenic molecules and regulatory mechanisms caused by BCR-ABL in two types of leukemia are different. It is reported that STAT6 was significantly activated only in P190 transformed cells. However, the potential role and the mechanism of STAT6 activation in Ph+ ALL and its activation mechanism by P190 are still unknown.MethodsThe protein and mRNA levels of STAT6, c-Myc, and other molecules were measured by western blot and quantitative real-time PCR. The STAT6 inhibitor AS1517499 was used to specifically inhibit p-STAT6. The effect of p-STAT6 inhibition on Ph+ CML and Ph+ ALL cells was identified by CCK-8 and FCM assay. Dual luciferase reporter and ChIP assay were performed to confirm the direct binding between STAT6 and c-Myc. The impact of STAT6 inhibition on tumor progression was detected in Ph+ CML and Ph+ ALL mouse models.ResultsOur results demonstrated that P210 induced CML-like disease, and P190 caused the more malignant ALL-like disease in mouse models. STAT6 was activated in P190 cell lines but not in P210 cell lines. Inhibition of STAT6 suppressed the malignancy of Ph+ ALL in vitro and in vivo, whereas it had little effect on Ph+ CML. We confirmed that p-STAT6 regulated the transcription of c-Myc, and STAT6 was phosphorylated by p-Jak2 in P190 cell lines, which accounted for the discrepant expression of p-STAT6 in P190 and P210 cell lines. STAT6 inhibition synergized with imatinib in Ph+ ALL cells.ConclusionsOur study suggests that STAT6 activation plays an essential role in the development of Ph+ ALL and may be a potential therapeutic target in Ph+ ALL. Video abstract.

Dataset Information

Role of Vitamins A and D in BCR-ABL Arf-/- Acute Lymphoblastic Leukemia.

Publications

Role of Vitamins A and D in BCR-ABL Arf<sup>-/-</sup> Acute Lymphoblastic Leukemia.

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Role of Vitamins A and D in BCR-ABL Arf-/- Acute Lymphoblastic Leukemia.

Publications

Role of Vitamins A and D in BCR-ABL Arf&lt;sup&gt;-/-&lt;/sup&gt; Acute Lymphoblastic Leukemia.

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Role of Vitamins A and D in BCR-ABL Arf<sup>-/-</sup> Acute Lymphoblastic Leukemia.