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Transcriptome profiling by RNA-sequencing of the AML cell line MOLM-13.

ABSTRACT: All-trans retinoic acid (ATRA, RA) has powerful activity in APL; its efficacy in non-APL AML is still unclear, but may be boosted by epigenetic drugs such azanucleoside DNMT inhibitors (Blagitko-Dorfs et al. PLoS ONE 2013). In a randomized phase II study (DECIDER trial, NCT00867672) the addition of RA to decitabine (DAC) in newly diagnosed non-fit older AML patients resulted in a clinically meaningful extension of survival. We hypothesize that in vitro, the add-on of RA to DAC results in cooperative transcriptome changes (possibly associated with demethylation), which may explain at least in part this clinical result.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184282 | GEO | 2022/08/31

REPOSITORIES: GEO

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Project description:All-trans retinoic acid (ATRA, RA) has powerful activity in APL; its efficacy in non-APL AML is still unclear, but may be boosted by epigenetic drugs such azanucleoside DNMT inhibitors (Blagitko-Dorfs et al. PLoS ONE 2013). In a randomized phase II study (DECIDER trial, NCT00867672) the addition of RA to decitabine (DAC) in newly diagnosed non-fit older AML patients resulted in a clinically meaningful extension of survival. We hypothesize that in vitro, the add-on of RA to DAC results in cooperative transcriptome changes (possibly associated with demethylation), which may explain at least in part this clinical result.

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Project description:Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) are enriched in CD34+CD38- fraction, and self-renewing LSCs hierarchically organize and maintain the AML populations. In acute promyelocytic leukemia (APL), which is driven by PML-RARα fusion genes, the presence of LSCs has long been unidentified, due to the difficulty of efficient reconstitution of human APL in the immunodeficient mice. Here, we show that LSCs of short type isoform APL, subtype of APL defined by different breakpoint of PML gene, concentrate in CD34+CD38- fraction and express T cell immunoglobulin mucin-3 (TIM-3) as in other non-APL AML. Short type APL cells exhibited distinct gene expression signatures including LSCs-related genes from other types of APL. Moreover, CD34+CD38-TIM-3+ short type APL cells efficiently reconstituted huma APL in xenograft models with high penetration, whereas CD34- more differentiated APL cells did not. Furthermore, CD34+CD38-TIM-3+ short type APL cells also reconstituted leukemia in the serial transplantation. Thus, short type APL is showing hierarchically organized by self-renewing APL-LSCs same as in other types of AML. The identification of LSCs in a subset of APL and establishment of efficient patient derived xenograft model would contribute to further understanding of APL leukemogenesis and devising individual treatment for eradication of APL LSCs.

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Treatment of AML patient samples with decitabine

Project description:Genome wide DNA methylation profiling of AML patient samples treated with PBS or DAC. The Illumina Infinium 450 Human DNA methylation was used to examine the methylation profile of 8 patient samples and 2 cell lines. Genome wide DNA methylation profiling of AML xenografts treated with either PBS control or with decitacine (DAC) alone, cytarabine (Ara-C) alone, DAC and Ara-C together (D+A), DAC followed by Ara-C (D/A) or with Ara-C followed by DAC (A/D).

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Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, often characterized by poor prognosis following standard induction therapy. The DNA methyltransferase inhibitor decitabine (DAC) is an alternative to intensive chemotherapy in elderly and relapsed/refractory AML patients. Despite some efficacy, DAC monotherapy does not promote complete remission and overall survival rates are very poor. Therefore, novel therapeutic regimens for AML are warranted. CD105 (endoglin), a receptor for the TGF-β superfamily, is expressed in various hematopoietic malignancies, including AML in which high expression correlates with poor prognosis. We have recently demonstrated that targeting CD105+ AML blasts with the TRC105 monoclonal antibody abrogates leukemogenesis in vivo. Based on these encouraging findings, here we investigated whether TRC105 in combination with DAC could represent a novel therapeutic option to treat relapsed/refractory AML. Treatment of leukemic mice with DAC in combination with TRC105 resulted in superior survival and significant reduction of leukemia burden in the bone marrow (BM) of AML xenografts compared to DAC monotherapy. To determine if TRC105 anti-leukemogenic effect is mediated by NK cells, we performed in vitro and in vivo studies. In the latter, we tested TRC105 in the context of NK depletion by injecting mice with an antibody to CD122. TRC105 treatment resulted in comparable reduction of leukemia burden in xenografts regardless of NK depletion, demonstrating that the anti-leukemogenic effect of TRC105 in AML is independent of NK cells. Altogether, our findings provide proof-of-principle for the clinical evaluation of TRC105 in combination with DAC in AML patients.

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