Acute promyelocytic leukemia (APL): remaining challenges towards a cure for all

Stahl, Maximilian; Tallman, Martin S.

doi:10.1080/10428194.2019.1613540

Cited by 71 publications

(67 citation statements)

References 61 publications

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“…The constitutive transcription activities of these hematopoietic progenitor cell factors could lead to the halt of differentiation of those progenitor cells and the transformation of lymphocytes. This mechanism is also similar to the mechanism very well characterized for acute promyelocytic leukemia (APL), in which, fusion of retinoic acid receptor‐α ( RARA ) on chromosome 17 is translocated in a reciprocal way to fuse with the promyelocytic leukemia gene ( PML ) on chromosome 15 and block the differentiation of myelocytic progenitor cells 138 . The exact opposite effect for RARA‐PML fusion with loss of differential factors occur in the APL, whereas constitutive expressions of stem maintenance factors happen in MLL‐fusions.…”

Section: A Third Underlying the Mechanism Of Mll‐fusions To Trigger Tmentioning

confidence: 57%

The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

Liu

Lee

Zhang

et al. 2020

Molecular Carcinogenesis

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A majority of infant and pediatric leukemias are caused by the mixed-lineage leukemia gene (MLL) fused with a variety of candidates. Several underlying mechanisms have been proposed. One currently popular view is that truncated MLL1 fusion and its associated complex constitutively hijacks super elongation complex, including positive transcription elongation factor b, CDK9, and cyclin T1 complex and DOT1L, to enhance the expression of transcription factors that maintain or restore stemness of leukocytes, as well as prevent the differentiation of hematopoietic progenitor cells. An alternative emerging view proposes that MLL1-fusion promotes the recruitment of TATA binding protein and RNA polymerase II (Pol II) initiation complex, so as to increase the expression levels of target genes. The fundamental mechanism of both theories are gain of function for truncated MLL1 fusions, either through Pol II elongation or initiation. Our recent progress in transcription regulation of paused Pol II through JMJD5, JMJD6, and JMJD7, combined with the repressive role of H3K4me3 revealed by others, prompted us to introduce a contrarian hypothesis: the failure to shut down transcribing units by MLL-fusions triggers the transformation: loss of function of truncated MLL1 fusions coupled with the loss of conversion of H3K4me1 to H3K4me3, leading to the constitutive expression of transcription factors that are in charge of maintenance of hematopoietic progenitor cells, may trigger the transformation of normal cells into cancer cells. Following this track, a potential treatment to eliminate these fusion proteins, which may ultimately cure the disease, is proposed. K E Y W O R D S CDK9, JMJD5, JMJD6, MLL-fusion, RNA polymerase II

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Section: A Third Underlying the Mechanism Of Mll‐fusions To Trigger Tmentioning

confidence: 57%

The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

Liu

Lee

Zhang

et al. 2020

Molecular Carcinogenesis

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“…Apart from ED, the relapse is another major challenge of APL, especially in high-risk patients ( 27 ). Until now, no consensus molecular cytogenetic abnormalities at the time of diagnosis can reliably predict the relapse, but monitoring PML-RARA transcripts after treatment is a confidential tool to predict relapse.…”

Section: Resultsmentioning

confidence: 99%

“…Details about this definition have been systematically reviewed in recent years (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). As a result of selection bias, clinical trial data have underestimated the impact of ED, but a series of epidemiologic studies revealed that a significant proportion of patients continue to suffer early death (27)(28)(29). Encouragingly, however, newer epidemiologic studies now suggest that ED rates may be improving (30)(31)(32)(33).…”

Section: Early Death Is the Major Obstacle To Curing All Patientsmentioning

confidence: 99%

The History of the Chemo-Free Model in the Treatment of Acute Promyelocytic Leukemia

Zhu

2020

Front. Oncol.

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Acute promyelocytic leukemia (APL) has become a highly curable disease after four decades of endeavors. Thanks to the efforts of investigators throughout the world, the chemo-free concept has become a reality for both low- and high-risk patients. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) without chemotherapy has become a first-line treatment for newly diagnosed APL and has been adopted in guidelines or expert recommendations from the NCCN and ELN and in China. Though the regimen has achieved great success, challenges still exist. The rate of early death still has not diminished significantly and is a major obstacle to curing all patients. Leukocytosis is the most important factor for ED, and completely abandoning chemotherapy is dangerous for certain patients in practice. To narrow the gap between guidelines and practice, this review aims to examine the history of the chemo-free model for the treatment of APL in the arsenic-alone era (1974–2002) and the arsenic plus ATRA era (2002–present) and provide practical considerations regarding early death.

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“…Arsenic trioxide, another anti-APL agent, has revolutionized APL treatments in relapsed/refractory disease. Remission with arsenic trioxide has also been reported [13]. Arsenic trioxide induces apoptosis regardless of PML-RARα status, but predominantly through the induction of mitotic arrest of the cell cycle and the mitochondria-mediated intrinsic apoptotic pathway without affecting the architecture of the microtubules [14].…”

Section: Introductionmentioning

confidence: 94%

Mechanistic Study of Triazole Based Aminodiol Derivatives in Leukemic Cells—Crosstalk between Mitochondrial Stress-Involved Apoptosis and Autophagy

Chan

Leu

Swain

et al. 2020

IJMS

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Various derivatives that mimic ceramide structures by introducing a triazole to connect the aminodiol moiety and long alkyl chain have been synthesized and screened for their anti-leukemia activity. SPS8 stood out among the derivatives, showing cytotoxic selectivity between leukemic cell lines and human peripheral blood mononuclear cells (about ten times). DAPI nuclear staining and H&E staining revealed DNA fragmentation under the action of SPS8. SPS8 induced an increase in intracellular Ca2+ levels and mitochondrial stress in HL-60 cells identified by the loss of mitochondrial membrane potential, transmission electron microscopy (TEM) examination, and altered expressions of Bcl-2 family proteins. SPS8 also induced autophagy through the detection of Atg5, beclin-1, and LC3 II protein expression, as well as TEM examination. Chloroquine, an autophagy inhibitor, promoted SPS8-induced apoptosis, suggesting the cytoprotective role of autophagy in hindering SPS8 from apoptosis. Furthermore, SPS8 was shown to alter the expressions of a variety of genes using a microarray analysis and volcano plot filtering. A further cellular signaling pathways analysis suggested that SPS8 induced several cellular processes in HL-60, including the sterol biosynthesis process and cholesterol biosynthesis process, and inhibited some cellular pathways, in which STAT3 was the most critical nuclear factor. Further identification revealed that SPS8 inhibited the phosphorylation of STAT3, representing the loss of cytoprotective activity. In conclusion, the data suggest that SPS8 induces both apoptosis and autophagy in leukemic cells, in which autophagy plays a cytoprotective role in impeding apoptosis. Moreover, the inhibition of STAT3 phosphorylation may support SPS8-induced anti-leukemic activity.

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Acute promyelocytic leukemia (APL): remaining challenges towards a cure for all

Cited by 71 publications

References 61 publications

The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

The History of the Chemo-Free Model in the Treatment of Acute Promyelocytic Leukemia

Mechanistic Study of Triazole Based Aminodiol Derivatives in Leukemic Cells—Crosstalk between Mitochondrial Stress-Involved Apoptosis and Autophagy

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