Acute promyelocytic leukemia (APL) is marked by a block at the promyelocyte stage. Treatments like ATRA and ATO face resistance and relapse issues. Plastrum testudinis, a traditional Chinese medicine, may offer therapeutic potential. This study investigated xtr-miR-22-3p from P. testudinis for treating APL. High expression of xtr-miR-22-3p was confirmed, with target prediction indicating interactions with key genes, including PML. xtr-miR-22-3p reduced HL-60 leukemia cell growth, altered the cell cycle, and selectively inhibited HL-60 proliferation while promoting BMSC growth, suggesting its potential as a targeted APL therapy.

Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation t (15;17) (q24;q21), which leads to the fusion of PML and RARα genes known as PML-RARα fusion. A few cases of potentially hereditary leukemia-related genes in APL have been reported, but no instances of familial aggregation of APL have been documented. Here, we describe a family in whom two members successively affected by APL。The potential familial association observed in these two cases of APL highlights the need for further investigation and more definitive genetic lineage tracing in order to understand the genetic basis of this disease.

The oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα) is critical for acute promyelocytic leukemia (APL). PML/RARα initiates APL by blocking the differentiation and increasing the self-renewal of leukemic cells. The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients. However, the emergence of mutations conferring resistance to ATRA and ATO has created challenges in the treatment of APL patients. Exploring pathways that modulate the oncogenic activity of PML/RARα could help develop novel therapeutic strategies for APL, particularly for drug-resistant APL. Herein, we demonstrated for the first time that palmitoylation of PML/RARα was a critical determinant of its oncogenic activity. PML/RARα palmitoylation was found to be catalyzed mainly by the palmitoyltransferase ZDHHC3. Mechanistically, ZDHHC3-mediated palmitoylation regulated the oncogenic transcriptional activity of PML/RARα and APL pathogenesis. The knockdown or overexpression of ZDHHC3 had respective effects on the expression of proliferation- and differentiation-related genes. Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.

OBJECTIVE: The objective of this study was to investigate the clinical characteristics and analysis of related factors associated with early death in newly diagnosed patients with acute promyelocytic leukemia (APL).
METHODS: This retrospective study included patients who visited our hospital between January 2010 and August 2022 and were diagnosed with APL for the first time. We analyzed their clinical and laboratory characteristics and analysis of related factors associated with early death.
RESULTS: A total of 269 patients with a primary diagnosis of APL were collected. The male to female ratio was 6:5, and the median age was 42 years (range 7-80). Among patients with initial APL diagnosis, there were 34 early deaths, resulting in an early mortality rate of 13%. The median time from diagnosis to death was 8.5 days (range 3-24). Comparative analysis of the clinical characteristics between patients who died early and those who did not, using a logistic regression model, revealed that age, white blood cell count (WBC) at initial diagnosis, and prolongation time of prothrombin time (PT) were independent risk factors for early death in patients with primary APL (P < 0.05). Comparing the clinical characteristics during hospitalization between the early death group and the non-early death group, it was observed that the daily mean of WBC during hospitalization was significantly higher in patients who died early than in those who did not (P < 0.001). Conversely, the daily mean of platelet count (PLT) was significantly lower in patients who died early compared to those who did not (P < 0.001). Furthermore, statistically significant differences were found in the mean daily infusion of PLT (P < 0.05), fibrinogen (Fib) (P < 0.05), and fresh frozen plasma (FFP) (P < 0.05) during hospitalization between patients who died early and those who did not. Specifically, the mean daily infusion of PLT and FFP was significantly higher in the early-death group than in the non-early-death group. Cerebral hemorrhage was identified as the immediate cause of death in 25 out of the 34 early-death patients (74%). The remaining causes of death included infection in 5 cases (15%), all of which were severe pulmonary infections, including 2 cases of combined differentiation syndrome, and abandonment of treatment in 4 patients (11%) at initial diagnosis.
CONCLUSIONS: In patients with primary APL, age, WBC at initial diagnosis, and PT prolongation time were identified as independent risk factors for early death (P < 0.05). Laboratory findings regarding WBC and PLT during hospitalization, as well as the infusion of PLT, Fib, and FFP during hospitalization, were also statistically significant. Cerebral hemorrhage was found to be the main cause of early death in patients with primary APL.

BACKGROUND: There is currently no standard treatment for relapsed and arsenic trioxide (ATO)-resistant acute promyelocytic leukemia (APL). Here, we report a case series of realgar-indigo naturalis formula (RIF) for the successful treatment of patients with relapsed and ATO-resistant APL.
METHODS: Two patients in the first relapse and one in the second relapse failed to achieve hematologic complete remission (HCR) when reinduced by ATO; the other five patients progressed to relapse during ATO-based regimens for post-remission therapy. These eight patients received RIF in three doses per day totaling 130 mg/kg (≤ 30 pills) as induction therapy and achieved HCR at a median time of 46.5 days. They received 5 years of post-remission therapy, which consisted of combined chemotherapy followed by RIF. During this period, the patients did not experience renal dysfunction or QT interval prolongation. At the last follow-up, three patients survived without relapse, two patients survived with a second or third relapse and third or fourth remission, and the other three patients relapsed for a third or fourth time and died. The 5-year overall survival and event-free survival rates were 75.0% (95% confidence interval [CI]: 31.5-93.1) and 37.5% (95% CI: 5.6-71.7), respectively.
CONCLUSIONS: RIF for induction therapy and RIF combined with chemotherapy for post-remission therapy may represent an effective and safe protocol for the treatment of patients with relapsed and ATO-resistant APL. Please cite this article as: Fang YG, Huang SL, Chen NN. Realgar-indigo naturalis formula for the treatment of patients with relapsed and arsenic trioxide-resistant acute promyelocytic leukemia: a case series. J Integr Med. 2024; Epub ahead of print.

Liver injury during arsenic treatment for acute promyelocytic leukemia was previously reported in adults, but not comprehensively in children until now. This study aims to investigate liver injury in pediatric patients with APL, changes in liver function during treatment, and compare the effects of Arsenic trioxide (ATO) and Realgar-Indigo naturalis formula (RIF) on liver function. One hundred and eighty-six patients with 3076 patient tests were analyzed, who were enrolled in the Chinese Children\'s Leukemia Group (CCLG)-APL2016 Protocol database between November 2016 and November 2018 in 38 hospitals across China(ChiCTR-OIN-17011227). Twenty of 164 patients (12.2%) suffered from liver injury after treatment with arsenic. In addition, sixteen (80%) cases of liver injury occurred during the induction period of treatment. What\'s not disheartening was that 18 (90%) cases of liver injury were transient, occurring at a median time of 17 days after exposure to arsenic. More importantly, the risk of liver injury associated with RIF was not higher than that associated with ATO (RR = 0.854, 95% CI: 0.292-2.495). Otherwise, the ALP of 18 cases of liver injury was not higher than the ULN of ALP. Thus, the incidence of liver injury associated with arsenic in pediatric patients with APL was similar to that in adult patients and the risk of liver injury associated with RIF was not higher than that associated with ATO. Since ALP was not higher in pediatric APL patients with liver injury, further research is needed to explore whether ALP is an index of liver injury in children.

Acute promyelocytic leukemia (APL), a distinctive subtype of acute myeloid leukemia (AML), is characterized by the t(15; 17) translocation forming the PML-RARα fusion protein. Recent studies have revealed a crucial role of retinoid X receptor α (RXRα) in PML-RARα\'s tumorigenesis. This necessitates the development of dual RARα and RXRα targeting compounds for treating APL. Here, we developed a pair of brominated retinoid isomers, 5a and 5b, exhibiting RARα agonistic selectivity among the RAR subtypes and RXRα partial agonistic activities. In the treatment of APL cells, low doses (RARα activation range) of 5a and 5b degrade PML-RARα and strongly induce differentiation, while higher doses (RXRα activation range) induce G2/M arrest and apoptosis in both all-trans retinoic acid (ATRA)-sensitive and resistant cells. We replaced the bromine in 5a with chlorine or iodine to obtain compounds 7 or 8a. Interestingly, the chlorinated compound 7 tends to activate RXRα and induce G2/M arrest and apoptosis, while the iodinated compound 8a tends to activate RARα and induce differentiation. Together, our work underscores several advantages and characteristics of halogens in the rational design of RARα and RXRα ligands, offering three promising drug candidates for treating both ATRA-sensitive and resistant APL.

In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion protein destroys PML nuclear bodies (NBs), leading to the formation of microspeckles. However, our understanding, largely learned from morphological observations, lacks insight into the mechanisms behind PML/RARα-mediated microspeckle formation and its role in APL leukemogenesis. This study presents evidence uncovering liquid-liquid phase separation (LLPS) as a key mechanism in the formation of PML/RARα-mediated microspeckles. This process is facilitated by the intrinsically disordered region containing a large portion of PML and a smaller segment of RARα. We demonstrate the coassembly of bromodomain-containing protein 4 (BRD4) within PML/RARα-mediated condensates, differing from wild-type PML-formed NBs. In the absence of PML/RARα, PML NBs and BRD4 puncta exist as two independent phases, but the presence of PML/RARα disrupts PML NBs and redistributes PML and BRD4 into a distinct phase, forming PML/RARα-assembled microspeckles. Genome-wide profiling reveals a PML/RARα-induced BRD4 redistribution across the genome, with preferential binding to super-enhancers and broad-promoters (SEBPs). Mechanistically, BRD4 is recruited by PML/RARα into nuclear condensates, facilitating BRD4 chromatin binding to exert transcriptional activation essential for APL survival. Perturbing LLPS through chemical inhibition (1, 6-hexanediol) significantly reduces chromatin co-occupancy of PML/RARα and BRD4, attenuating their target gene activation. Finally, a series of experimental validations in primary APL patient samples confirm that PML/RARα forms microspeckles through condensates, recruits BRD4 to coassemble condensates, and co-occupies SEBP regions. Our findings elucidate the biophysical, pathological, and transcriptional dynamics of PML/RARα-assembled microspeckles, underscoring the importance of BRD4 in mediating transcriptional activation that enables PML/RARα to initiate APL.

UNASSIGNED: Acute promyelocytic leukemia (APL) is a distinct form of acute myeloid leukemia characterized by the presence of t(15;17)(q24;21) and the PML:RARA gene fusion. Frontline use of intravenous arsenic trioxide (i.v.-ATO) and all-trans retinoic acid (ATRA) has vastly improved cure rates in APL. Researchers in Hong Kong invented the oral formulation of ATO (oral-ATO) and have confirmed a bioavailability comparable to i.v.-ATO. A plethora of studies have confirmed the safety and efficacy of oral-ATO-based regimens in the frontline and relapsed setting.
UNASSIGNED: Aspects on the development of oral-ATO-based regimens for APL in the frontline and relapsed setting are discussed. The short-term and long-term safety and efficacy of oral-ATO-based regimens are discussed. The frontline use of oral-ATO in combination with ATRA and ascorbic acid (AAA) induction in a \'chemotherapy-free\' is highlighted.
UNASSIGNED: Current and ongoing data on the use of oral-ATO-based regimens in APL support the use of oral-ATO as an alternative to i.v.-ATO allowing a more convenient and economical approach to the management of APL.

OBJECTIVE: To investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism.
METHODS: The GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined.
RESULTS: The expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells.
CONCLUSIONS: ATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects.