AbstractAcute Promyelocytic Leukemia Research Articles

Abstract 5317: A novel approach to the treatment of ATRA/ATO resistant acute promyelocytic leukemia

Abstract Acute Promyelocytic Leukemia (APL) is characterized by proliferation of immature promyelocytes. Combination therapy using retinoic acid (RA) and arsenic trioxide (ATO) is considered standard treatment in the clinical environment. Resistance to both RA and ATO is associated with an increased risk of mortality. In addition, relapse occurs in approximately 10-20% of patients undergoing treatment for APL. Growth Hormone Releasing Hormone (GHRH) is a hypothalamic peptide that stimulates the release of Growth Hormone from the anterior pituitary. Our previous studies have demonstrated that human AML cell lines (K-562, THP-1, and KG-1a) display the GHRH receptor (GHRH-R). Incubation with GHRH-R antagonist MIA-602, inhibited proliferation and induced apoptosis. The purpose of this study is to examine the effects of GHRH-R antagonist MIA-602, on the NB4 Human Promyelocytic Leukemia cell line and its ATRA and ATO resistant sub-clone. NB4 cells expressed both GHRH-R and SV1 variants via western blot analysis. Wild type NB4 cells, as well as NB4 cells resistant to both ATRA and ATO (NB4-RAA), were cultured in suspension in RPMI and 10% fetal calf serum. NB4-RAA were established in Dr. Jimenez's lab from the wild type NB4 parent cell line. NB4 and NB4-RAA were plated in triplicate on multi-wells at 50,000 cells/mL. Cell lysates were prepared after incubation with 0.05-5 µmol/L of MIA-602. Cell viability was measured at 24 and 48h. Flow cytometry was also performed on the naïve NB4 parent cell line in addition to NB4-RAA to assess expression of CD-56 the cell surface marker. Upregulation of CD-56, also known as Neural cell adhesion molecule 1 (NCAM-1), has been shown to confer drug resistance in AML and is an important prognostic marker in APL. The viability of both cell lines decreased to similar levels at 24 h and 48 h when exposed to concentrations of MIA-602 higher than 0.05 μmol/L (p < 0.05). A significant decrease in cell viability was seen above 0.5 μmol/L after 48h. No viable cells were found in either cell line after 48h when exposed to 5 μmol/L of MIA-602. No difference in cell viability was found between naïve NB4 and resistant NB4-RAA when exposed to the same concentrations of MIA-602. MIA-602 induced significant changes in the expression level of many death-related genes including CASP9 (>1.5-fold; P<0.05). Results of flow cytometry revealed significantly increased expression of CD-56 (>5.8-fold; p,0.05) in NB4-RAA cells as compared to the parent cell line. These results indicate that resistance to ATRA and ATO in APL cells does not confer subsequent resistance to MIA-602. As a result, MIA-602 targets a pathway that is distinct from that of ATRA & ATO. More importantly, upregulation of pro-apoptotic genes by MIA-602 indicates an alternative pathway elicited by the GHRH-R antagonist in the setting of resistant APL cells. Our results indicate that the resistance to frontline APL therapy can be effectively overcome by using MIA-602. Citation Format: Ravinder S. Chale, Stephanie M. Almeida, Ivan Jozic, Andrew V. Schally, Joaquin J. Jimenez. A novel approach to the treatment of ATRA/ATO resistant acute promyelocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5317.

Comment on Geoffroy, M.-C.; de Thé, H. Classic and Variants APLs, as Viewed from a Therapy Response. Cancers 2020, 12, 967.

Acute promyelocytic leukemia (APL) is a unique and very deeply studied acute myeloid leukemia [...].

Practice patterns and real-life outcomes for patients with acute promyelocytic leukemia in the United States

Acute promyelocytic leukemia (APL) is associated with a favorable long-term prognosis if appropriate treatment is initiated promptly. Outcomes in clinical trials and population-based registries vary; potential explanations include a delay in treatment and lower adherence to guideline-recommended therapy in real-world practice. We used the Vizient Clinical Data Base to describe demographic characteristics, baseline clinical characteristics, and treatment patterns in patients newly diagnosed with APL during the study period of April 2017 to March 2020. Baseline white blood cell count was used to assign risk status and assess treatment concordance with National Comprehensive Cancer Network guidelines. Logistic regression models examined adjusted associations between patient, hospital, disease characteristics, and adverse outcomes (in-hospital death or discharge to hospice). Among 1464 patients with APL, 205 (14.0%) experienced an adverse outcome. A substantial subset (20.6%) of patients did not receive guideline-concordant regimens. Odds of adverse outcomes increased with failure to receive guideline-concordant treatment (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.43-3.75; P = .001), high-risk disease (OR, 2.48; 95% CI, 1.53-4.00; P < .001), and increasing age (≥60 years: OR, 11.13; 95% CI, 4.55-27.22; P < .001). Higher hospital acute myeloid leukemia (AML) patient volume was associated with lower odds of adverse outcome (OR, 0.44; 95% CI, 0.20-0.99 [for ≤50 vs >200 AML patients per year]; P = .046). In conclusion, in this large database analysis, 14.0% of patients newly diagnosed with APL died or were discharged to hospice. A substantial proportion of patients did not receive guideline-concordant therapy, potentially contributing to adverse outcomes.

Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), classified by a translocation between chromosomes 15 and 17 [t(15;17)], that is considered a true oncologic emergency though appropriate therapy is considered curative. Therapy is often initiated on clinical suspicion, informed by both clinical presentation as well as direct visualization of the peripheral smear. We hypothesized that genomic imprinting of morphologic features learned by deep learning pattern recognition would have greater discriminatory power and consistency compared to humans, thereby facilitating identification of t(15;17) positive APL. By applying both cell-level and patient-level classification linked to t(15;17) PML/RARA ground-truth, we demonstrate that deep learning is capable of distinguishing APL in both discovery and prospective independent cohort of patients. Furthermore, we extract learned information from the trained network to identify previously undescribed morphological features of APL. The deep learning method we describe herein potentially allows a rapid, explainable, and accurate physician-aid for diagnosing APL at the time of presentation in any resource-poor or -rich medical setting given the universally available peripheral smear.

Early mortality and overall survival in acute promyelocytic leukemia – a single-center experience

Acute promyelocytic leukemia (APL) is a subtype of acute leukemia (AL) with distinct cytogenetics, clinical and biological characteristics. APL was considered as one of the most rapidly lethal forms of acute myeloblastic leukemia (AML), but recently, with the introduction of all-trans retinoic acid (ATRA) it has become the most curable subtype of AL. The main difficulty with APL is early death (ED), defined as death because of any cause within 30 days after diagnosis, and it has emerged as the most important cause of treatment failure. Our retrospective-prospective study was realized at the University Clinic for Hematology from January 2004 until December 2020. It included 46 patients with APL, according to FAB and WHO classification with confirmed molecular diagnosis. The following patients’ risk stratification factors were analyzed: age, Sanz risk score, WBC, PL, clinical presentation of the disease, levels of fibrinogen and D-dimers. During the study period, APL was diagnosed in 46 patients, 24 females (52.2%) and 22 males (47.8%), with mean age of 45 years. The overall survival showed that 24 patients (52.1%) were alive and 22 (47.8%) had lethal outcome. Regarding treatment, five patients (10.9%) died before starting the chemo-treatment. But, still, ED was observed in 13 patients (59%), and in 9 patients (40.9%) death occurred 30 days after establishing the diagnosis. The main reasons of mortality were also analyzed. To prevent ED prior to treatment, suspected APL patients should be immediately hospitalized and treated as medical emergency. Keywords: acute promyelocytic leukemia, early death, all-trans retinoic acid

Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) cytogenetically characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between the promyelocytic leukemia (PML) gene and retinoic acid receptor-α (RARα) [...]

Sequential Treatment of Arsenic Trioxide Followed by All Trans Retinoic Acid with Anthracyclines has Excellent Long-Term Cure in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) remains the most curable myeloid leukemia made feasible through effective use of two differentiating agents, all trans retinoic acid (ATRA) and arsenic trioxide (ATO) with or without chemotherapy (CT). However, early morbidity and mortality remains a problem. With the objective of reducing early death a strategy of sequential induction ATO followed by consolidation ATRA in combination with CT was adopted by our group. The long-term outcomes of patient of APL treated on this sequential approach at our center was analyzed. In this retrospective analysis of prospectively maintained database consecutive adult patients with APL irrespective of their Sanz risk group were treated using a protocol of ATO (10 mg IV infusion over 3 h daily for 45 days) in the first phase followed by ATRA (45 mg/m2 for 60 days) in combination with Daunorubicin (60 mg/m2 for 3 days × 3 cycles) in second phase. All patients received maintenance ATRA (45 m/m2 for 15 days every 3 months) for a period of 18 months in phase 3. Patients were monitored for cytogenetic and molecular responses after phase 1 and 2. All patients were followed up for toxicity, event free and overall survival. 131 consecutive patients were treated in this study. At a median follow up of 60 months, 84.81% patients are alive with an overall event free survival (EFS) of 77.82%. Sanz low risk patients fared better (85%) versus intermediate and high-risk patients who had a 76% EFS. Proportion of patients alive at last follow up were 100% in Sanz low risk group and 82% in intermediate and high-risk group. The sequential schedule showed excellent tolerance and toxicity profile when treating newly diagnosed APL. The long-term follow-up data shows comparable if not better survival compared with the published real-world data and this has been consistent across all risk group.

Pregnancy Complicated with Acute Promyelocytic Leukemia: A Case Report and a Literature Review

Acute promyelocytic leukemia (APL) is a special subgroup of acute myeloid leukemia (AML). About 95% of the patients have specific chromosome translocation t (15 ≤ 17) (q22, q12). APL progresses rapidly and is characterized by extensive and severe bleeding and disseminated intravascular coagulation (DIC). Patients may present with severe clinical manifestation which is often caused by the occurrence of DIC in the early stages of the disease. Pregnancy complicated with APL is rare in the clinical setting. They have many complications, high mortality and are difficult to manage clinically. This case report describes a case of a primary pregnancy complicated with APL, in order to better understand how to manage such complex cases.

Abstract 4406: TRIB3 stabilizes high TWIST1 expression to promote rapid APL progression &amp; ATRA resistance

Abstract Acute promyelocytic leukemia (APL), which accounts for 10-15% of acute myeloid leukemia (AML) cases, is characterized by the t (15; 17) chromosomal translocation and is now highly curable by the combination of granulocytic differentiation induction and the PML-RARα oncoprotein-targeted agents all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Despite the striking molecular complete remission (CR) and the very few cases of relapse associated with ATRA/ATO-based regimens, mortality events typically result from early fatal bleeding, which remains the most important challenge and the largest obstacle to curing all APL patients. For instance, several studies have reported that the risk of early hemorrhagic death (HD) reaches an incidence of 10-20% during the first month of induction. Importantly, APL patients with a high white blood cell count face an increased risk of early HD. Furthermore, differentiation syndrome and resistance to ATRA/ATO treatment with PML-RARα mutations still endanger the health of a significant proportion of APL patients. Thus, we need to better understand the molecular mechanism of APL pathogenesis and design more effective therapeutic strategies to block the rapid progression of early HD and overcome resistance. Oncogenic transcription factors play an important role in the development of hematological malignancy. The dysregulation of epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs), including SNAI1/SNAI2, ZEB1/ZEB2 and TWIST1/TWIST2, which are closely related to malignant progression in solid tumors, has also been explored in the context of the aggressive invasion, chemoresistance and poor prognosis of AML. In this study, we found through two database (TCGA and E-MTAB-344) gene expression searches and detailed functional verification that the EMT-TF TWIST1 is highly expressed in APL cells and is critical for leukemic cell survival. TWIST1 and TRIB3 were highly coexpressed in APL cells compared with other subtypes of AML. We subsequently demonstrated that TRIB3 could bind the bHLH and WR domains of TWIST1 and stabilize TWIST1 by inhibiting the ubiquitination of the TWIST1 protein. Based on a detailed analysis of a functional screen of synthetic peptides, we discovered a peptide analogous to the previously reported TWIST1 WR domain, which rapidly and specifically represses APL cell survival through disrupting the TRIB3/TWIST1 interaction. Our data also suggest that a peptide similar to the WR domain disturbs the TRIB3/TWIST1 interaction, impairs rapid progression during the early death of APL and reverses resistance to ATRA therapy. These results reveal the important role of a specific oncogenic transcriptional factor, TWIST1, in APL leukemogenesis and suggest a potential peptide-initiated rapid proteolysis therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL. Citation Format: Wu Zhang, Jian Lin, Jie Xu. TRIB3 stabilizes high TWIST1 expression to promote rapid APL progression &amp; ATRA resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4406.

Real life outcomes of patients aged ≥75 years old with acute promyelocytic leukemia: experience of the PETHEMA registry

Acute promyelocytic leukemia is infrequent among patients aged ≥75 years old, a population that is rarely eligible for clinical protocols. This study aims to analyze the treatment strategies and clinical outcomes of very old APL patients reported to the international PETHEMA registry. Between 1997 and 2017, among 2501 APL cases registered 120 were ≥75 years old. Treatment approaches were: AIDA regimen, 79 patients; ATRA alone, 23; 16, supportive care (SC) and 2, other strategies. Patients treated with AIDA were younger, had better ECOG and lower leukocytes. Complete remission (CR) was achieved in 65% of AIDA-group vs. 45% in the ATRA-group, being infections followed by bleeding the most frequent causes of induction death. Patients in CR after AIDA showed 3-year DFS of 73%. Our real-life series of very old APL patients provides a reference basis for future treatment strategies aiming to improve clinical outcomes in this challenging population.

A novel flow cytometric method for enhancing acute promyelocytic leukemia screening by multidimensional dot-plots

Acute promyelocytic leukemia (APL) is generally characterized by t(15;17)(q24;q21). In some cases, the classic translocation cannot be identified by conventional methods, since the PML-RARA fusion protein results from complex, variant, or cryptic translocation. The diagnostic algorithm of APL starts with screening methods, such as flow cytometry (FC), followed by fluorescence in situ hybridization or polymerase chain reaction to confirm the diagnosis. Our aim was to develop a novel protocol for analyzing APL samples based on multidimensional dot-plots that can provide comprehensive information about several markers at the same time. The protocol included four optimized multidimensional dot-plots, which were tested by retrospective reanalysis of FC results in APL (n = 8) and non-APL (n = 12) acute myeloid leukemia (AML) cases. After predicting the potential position of hypergranular- and microgranular-type aberrant promyelocytes, the percentages of blast populations were examined within the gates in all AML cases. The percentage of blasts in each predefined gate was well above the cut-off value (95%) in APL cases in all tubes. In non-APL AML cases, the percentage of blasts in the same gates never reached the cut-off value in all investigated tubes, and even when it did in a single tube, the pattern was markedly different from that observed in APL cases. In conclusion, multidimensional dot-plots can be used for screening APL even in cryptic APL cases, although reproducibility across several laboratories would require standardization of antibodies and fluorochromes. This easy-to-use and quick method can support the diagnosis of APL and the prompt initiation of the appropriate treatment.

Abstract 1506: Characterization of fibronectin type III domain containing 3B (FNDC3B) as a novel fusion partner of retinoic acid receptor alpha in granulocytic differentiation

Abstract Acute promyelocytic leukemia (APL) is characterized by the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) fusion. Recently, we identified fibronectin type III domain containing 3B (FNDC3B) as a novel RARA fusion partner resulting from the t(3;17)(q26;q21) translocation in a variant APL patient. Unlike other RARA fusion partners, FNDC3B appears as the only partner involved in granulocytic differentiation but the molecular mechanisms underlying its actions remain to be characterized. FNDC3B mRNA expression in normal and malignant hematopoietic cells was determined by quantitative RT-PCR. Transcriptional control of FNDC3B was studied by reporter gene assays, site-directed mutagenesis and chromatin immunoprecipitation (ChIP) assays. FNDC3B-regulated pathways were identified by transcriptome analyses. Using BloodSpot, we observed that FNDC3B expression was progressively up-regulated as human hematopoietic stem cells (HSCs) differentiate along the granulocytic lineage, with the highest level in terminally differentiated polymorphonuclear cells. Concordantly, we demonstrated lower expression of FNDC3B in human cord blood CD34+ HSCs than HL-60 promyelocytes. The specific involvement of FNDC3B in granulocytic differentiation was further suggested by higher FNDC3B expression and promoter activity in human promyelocytic than monocytic cell lines. Mutational analyses indicated that two putative CCAAT-enhancer binding protein epsilon (CEBPE) and one Sp1 binding sites were critical for FNDC3B promoter activity in HL-60 cells. The specific association of CEBPE and Sp1 with the FNDC3B promoter could be confirmed by ChIP assays. Knockdown of CEBPE in HL60 cells by small interfering RNA (siRNA) reduced FNDC3B expression and promoter activity. Furthermore, we observed a strong positive correlation between CEBPE and FNDC3B expression in the Cancer Genome Atlas (TCGA)-acute myeloid leukemia (AML) dataset (n=173, r=0.66, P&amp;lt;0.0001). Collectively, these findings indicate CEBPE, which is critical in terminal granulopoiesis, as an important factor controlling FNDC3B transcription in granulocytic cells. Using RNA-seq, we found that FNDC3B knockdown in NB4 promyelocytes was associated with preferential downregulation of genes encoding granule and endoplasmic reticulum (ER) structural/functional proteins. Concordantly, DAVID functional annotation of genes that are positively correlated with FNDC3B in the TCGA-AML cohort revealed enrichment of Gene Ontology terms related to ER functions. Together, these findings suggest that FNDC3B mediates its functions primarily by targeting the ER/granule pathway, which is important for granulocytic maturation. In summary, our data indicate FNDC3B as a novel CEBPE target in the myeloid transcriptional hierarchy and may provide new clues in abnormal granulopoiesis. Citation Format: Zhe Wand, Chi Keung Cheng, Terry Wong, Kin Mang Lau, Thomas S.k. Wan, Kam Tong Leung, Margaret Heung-Ling Ng. Characterization of fibronectin type III domain containing 3B (FNDC3B) as a novel fusion partner of retinoic acid receptor alpha in granulocytic differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1506.

Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is the most malignant form of acute leukemia, relatively uncommon in children, rapidly fatal if untreated and several developments have paved the way to make this disease curable. We report a first case to our knowledge in Nepal, a 12 years old boy who was diagnosed as APL and treated with vesanoid 14 years back and has been free from disease till date.

Effect of N’-Acetylindirubin on Proliferation, Apoptosis and Cell Cycle in Acute Myeloid Leukemia HL-60 Cells

Acute promyelocytic leukemia (APL) is a severe type of acute leukemia and the prognosis of patients was poor. Indirubin is the active constituent of the traditional Chinese medicine qingdai and an indoline anti-tumor drug. N’-Acetylindirubin is a novel indirubin derivative with better curative effect and less side effect. In this study, the effects of N’-Acetylindirubin on proliferation, apoptosis and cell cycle of acute myeloid leukemia cell line HL-60 was examined. The results demonstrated that N’-Acetylindirubin significantly induced apoptotic cell death in a dose and time-dependent manner and arrested cell cycle in G2/M in HL-60 cells. N’-Acetylindirubin also suppressed cyclin D1. This study suggests that N’-Acetylindirubin may serves as a potential chemopreventive agent for acute promyelocytic leukemia.

A Rare Case of Acute Promyelocytic Leukemia With Focal Bone Marrow Involvement Presenting as a Paraspinal Myeloid Sarcoma

Acute promyelocytic leukemia (APL) accounts for 5–8% of acute myeloid leukemias (AMLs). Myeloid sarcomas (MS) are rare extramedullary tumors consisting of immature myeloid cells. These tumors may develop de novo or concurrently with AML and may precede or coincide with the occurrence of AML. The occurrence of MS in an APL patient is a rare clinical event. In these cases, it usually occurs as a sign of relapse. Focal bone marrow involvement by APL is also rare; the majority of cases of APL demonstrate a diffusely hypercellular bone marrow throughout the axial skeleton due to expansion of neoplastic blasts/promyelocytes. We describe a 23-year-old female who presented with gait problems, including multiple falling episodes, and lower extremity weakness. An MRI demonstrated a paraspinal soft tissue mass. Histopathologic analysis demonstrated a myeloid sarcoma expressing CD45, myeloperoxidase, CD117, BCL2, focal weak CD34, and weak CD99 and negative for CD30, TdT, CD20, CD3, and CD10. The bone marrow aspirate demonstrated blasts/promyelocytes accounting for approximately 26% of the total bone marrow aspirate cellularity. The bone marrow biopsy and clot section demonstrated normocellularity with a few blast/promyelocyte foci on the clot section accounting for approximately 5% of total bone marrow cellularity. These foci expressed MPO and CD117 and were negative for CD34. Flow cytometry demonstrated blasts accounting for approximately 31% of all CD45+ events expressing MPO, CD33, CD13, CD117, CD64, CD2, CD38, and CD71 and negative for CD34, HLA-DR, CD11b, CD14, CD15, CD16, CD19, CD22, CD10, CD56, CD61, and surface and cytoplasmic CD3. Fluorescence in situ hybridization (FISH) analysis was positive for the t(15;17)(q22;q12) promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) translocation. The patient was induced with arsenic trioxide and subsequently underwent consolidation chemotherapy with daunorubicin and all-trans-retinoic acid. Her post-chemotherapy bone marrow biopsy was negative for residual disease. Flow cytometry and FISH analysis were also negative. This is a rare case of APL involving both the initial presentation as myeloid sarcoma and focal bone marrow involvement.

Acute promyelocytic leukemia with isochromosome 17q and cryptic PML-RARA successfully treated with all-trans retinoic acid and arsenic trioxide

Acute promyelocytic leukemia (APL) is a subtype of acute leukemia that is characterized by typical morphology, bleeding events and distinct chromosomal aberrations, usually the t(15;17)(q22;q21) translocation. Approximately 9% of APL patients harbor other translocations involving chromosome 17, such as the t(11;17)(q23;q21), t(5;17)(q35;q12-21), t(11;17)(q13;q21), and der(17). All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have specific targeted activities against the PML-RARA fusion protein. The combination of ATRA and ATO is reportedly superior to chemotherapy and ATRA as induction therapy for APL. The clinical significance of non-t(15:17) APL-related aberrations is controversial, with conflicting reports regarding sensitivity to modern, targeted therapy. Isochromosome 17q (iso(17q)) is rarely associated with APL and usually occurs concurrently with the t(15:17) translocation. No published data is available regarding the efficacy of ATO-based therapy for APL patients who harbor iso(17q). We report on an APL patient with iso(17q) as the sole cytogenetic aberration and a cryptic PML-RARA transcript, who was treated with ATRA and ATO after failure of chemotherapy and achieved complete remission. To our knowledge, this is the first published report of APL associated with iso(17q) as the sole cytogenetic aberration, which was successfully treated with an ATO containing regimen.

Fluroscence in-situ hybridization negative PML/RARA: A cryptic puzzle

Acute promyelocytic leukemia (APL) has defined biology and clinical course that is, distinct from the other forms of acute myelogenous leukemia. It may present with potentially devastating coagulopathy and the sensitivity to retinoid differentiating agents, including all-trans retinoic acid and arsenic trioxide, hence a fast and definite diagnosis is imperative. Reciprocal 15, 17 translocation creates a PML/RARA fusion gene on the derivative chromosome 15, which can be detected by various molecular tests such as cytogenetics, fluroscence in-situ hybridization (FISH), reverse transcriptase-polymerase chain reaction. We present here a diagnostically challenging case, both morphologically and immunophenotypically proven to be APL, which was negative for the PML/RARA by FISH.

MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by the t(15;17)-associated PML-RARA fusion gene. We have previously found that MIR125B1 is highly expressed in patients with APL and may be associated with disease pathogenesis; however, the mechanism by which MIR125B1 exerts its oncogenic potential has not been fully elucidated. Here, we demonstrated that MIR125B1 abundance correlates with the PML-RARA status. MIR125B1 overexpression enhanced PML-RARA expression and inhibited the ATRA-induced degradation of the PML-RARA oncoprotein. RNA-seq analysis revealed a direct link between the PML-RARA degradation pathway and MIR125B1-arrested differentiation. We further demonstrated that the MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of APL differentiation. Furthermore, we identified DRAM2 (DNA-damage regulated autophagy modulator 2), a critical regulator of autophagy, as a novel target that was at least partly responsible for the function of MIR125B1 involved in autophagy. Importantly, the knockdown phenotypes for DRAM2 are similar to the effects of overexpressing MIR125B1 as impairment of PML-RARA degradation, inhibition of autophagy, and myeloid cell differentiation arrest. These effects of MIR125B1 and its target DRAM2 were further confirmed in an APL mouse model. Thus, MIR125B1 dysregulation may interfere with the effectiveness of ATRA-mediated differentiation through an autophagy-dependent pathway, representing a novel potential APL therapeutic target.

Acute Promyelocytic Leukemia in a 17yr Male presenting as Intracerebral Haemorrhage

Acute promyelocytic leukemia (APML), once highly fatal, has emerged as the most curable subtype of acute myeloid leukemia in adults. Early mortality most often is due to a severe catastrophic bleeding, often intracerebral in location. Here we report a 17year male patient presented with status epilepticus having high leukocyte count (3,28,000/mm3) and low platelet count(34,000/mm3).Peripheral blood &amp; bone marrow was showing good no. of atypical promyelocytes. CT scan of brain revealed an intracerebral haemorrhage with laboratory profile of prolonged prothrombin time and activated partial thromboplastin time, the presence of Ddimer and decreased fibrinogen concentration. The patient was diagnosed as Acute Promyelocytic Leukemia with Intracerebral haemorrhage. The patient died on the same day. APML is the notorious subtype of acute myeloid leukemia which causes fatal intracranial haemorrhage which has high mortality and morbidity. Clinically significant coagulopathy is present in 70%– 80% of APML patients at the time of diagnosis. Early detection and aggressive correction of coagulopathy may prevent the catastrophic event. Prompt image study for locations and types of ICH can predict outcomes. DOI: http://dx.doi.org/10.3329/bjms.v13i1.14482 Bangladesh Journal of Medical Science Vol. 13 No. 01 January2014: 88-90

Treatment of acute promyelocytic leukemia with arsenic trioxide: clinical results and open questions

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia. The specific translocation t(15;17), which results in the fusion gene PML–RARA is the diagnostic and pathomechanistic hallmark of APL. By combination, treatment consisting of the differentiating agent all-trans retinoic acid (ATRA), which targets this molecular lesion, and cytotoxic chemotherapy, cure can be achieved in over 70% of patients. Recently, arsenic trioxide (ATO) has emerged to be the most active single agent in the treatment of APL. Previous studies employing ATO in relapse settings reported average complete remission rates of 85% and a mean overall survival of over 60%. In recent approaches installing ATO in first-line treatment, ATO-induced response rates comparable to previous combination regimen. The results of these newer studies indicate that the backbone of chemotherapy can be dramatically reduced or completely replaced by ATO and ATRA with similar or even better outcome.