Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes.

Advancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) towards precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifiers genes and activated signaling/myeloid transcription factor (AS/MTF), with disease progression and treatment failure in CML patients following tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML samples were sequenced, including 254 samples collected at initial diagnosis, and 140 samples taken during follow-up. Single-molecule molecular inversion probe (smMIP)-based next-generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes with a limit of detection of 0.2%. A total of 70 mutations were detected in 57 (22.4%) diagnostic samples, while 64 mutations were detected in 39 (27.9%) of the follow-up samples. Carrying any mutation at initial diagnosis was associated with worse outcomes following TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with Imatinib showed higher risks of treatment failure (HR 2.53, 95% CI [1.13-5.66], p=0.0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs (2G-TKI). The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival (FFS), and progression risk. Additionally, there was an observable non-significant trend indicating a heightened risk of progression to advanced disease and worse overall survival (OS). Conclusion: Mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression, even from initial diagnosis, and may help upfront TKI selection.

Telomeric repeat-containing RNA is dysregulated in acute myeloid leukemia.

TERRA (telomeric repeat-containing RNA) is a class of long noncoding RNAs transcribed from subtelomeric and telomeric regions. TERRA binds to the subtelomeric and telomeric DNA-forming R-loops (DNA-RNA hybrids), which are involved in telomere maintenance and telomerase function, but the role of TERRA in human cells is not well characterized. Here, we comprehensively investigated for the first time TERRA expression in primary human hematopoietic cells from an exploratory cohort of patients with acute myeloid leukemia (AML), patients with acute lymphoblastic leukemia (ALL), patients with telomere biology disorder (TBD), and healthy subjects. TERRA expression was repressed in primary human hematopoietic cells, including healthy donors, patients with ALL, and patients with TBD, irrespective of their telomere length, except for AML. A second cohort comprising 88 patients with AML showed that TERRA was overexpressed in an AML subgroup also characterized by higher R-loop formation, low TERT and RNAseH2 expression, and a paucity of somatic splicing factor mutations. Telomere length did not correlate with TERRA expression levels. To assess the role of TERRA R-loops in AML, we induced R-loop depletion by increasing RNAseH1 expression in 2 AML cell lines. Decreased TERRA R-loops in AML cell lines resulted in increased chemosensitivity to cytarabine. Our findings indicate that TERRA is uniformly repressed in primary human hematopoietic cells but abnormally expressed in an AML subset with low telomerase.

Peripheral lymphocyte subsets as predicting factors for molecular recurrence after imatinib discontinuation in a phase 2 imatinib discontinuation trial in patients with chronic myeloid leukemia.

INTRODUCTION: Treatment-free remission (TFR) is successful in half of the patients with chronic myeloid leukemia who discontinue Imatinib (IM) after sustained molecular response. METHODS: In a prospective trial, we used pioglitazone for 3 months before stopping IM in 30 patients. Percentages of peripheral blood lymphocyte subsets were assessed before and after treatment. The relation of these data with duration of IM treatment and TRF were examined. RESULTS: The median time of IM treatment was 117.6 months. After discontinuation, 11 patients had molecular recurrence after 5.2 months (2.4 - 30). The observation time for those remaining in TFR was 46 (26 - 56) months. The independent factors for the maintenance of TFR were the duration of IM treatment and the percentage of double-positive T cells at IM stop. CONCLUSION: A longer treatment with imatinib was associated with a longer TFR after discontinuation. Pioglitazone could act as an immunomodulator, increasing DP T cells which may contribute to prevent relapse.

Treatment patterns and outcomes for Hodgkin Lymphoma patients aged 60 and older: a report from the Brazilian Prospective Hodgkin Lymphoma Registry.

The treatment of older patients with Hodgkin lymphoma (HL) remains a challenge. We sought to identify the treatment patterns and outcomes in older HL patients included in the Brazilian HL registry (NCT02589548). A total of 136 patients with HIV-negative classic HL, aged ≥ 60 years, diagnosed between 2009 and 2018, were analyzed. The median age was 66 years old (60-90), 72% had advanced disease, 62% had a high IPS, and 49% had a nodular sclerosis subtype. Median follow-up was 64 months for alive patients. ABVD was the front-line treatment in 96% of patients. Twenty-one patients (15%) died during front-line treatment. The 5-year PFS and 5-year OS rates were 55% and 59%, respectively. The 5-year OS rates in localized and advanced disease were 81% and 51% (p=0.013). Lung toxicity developed in 11% of the patients treated with ABVD. Bleomycin was administered for > 2 cycles in 65% of patients. Compared with 2009-2014, there was a decrease in the use of bleomycin for > 2 cycles in 2015-2018 (88% × 45%, p<0.0001). The impact of socioeconomic status (SES) on outcomes was studied in patients treated with ABVD. After adjusting for potential confounders, lower SES remained independently associated with poorer survival (HR 2.22 [1.14-4.31] for OS and HR 2.84 [1.48-5.45] for PFS). Treatment outcomes were inferior to those observed in developed countries. These inferior outcomes were due to an excess of deaths during front-line treatment and the excessive use of bleomycin. SES was an independent factor for shorter survival.

Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia.

Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.

Diagnosis and treatment of systemic mastocytosis in Brazil: Recommendations of a multidisciplinary expert panel

ABSTRACT Introduction: Systemic Mastocytosis comprises a group of neoplastic diseases characterized by clonal expansion and infiltration of mast cells into several organs. The diagnosis and treatment of this disease may be challenging for non-specialists. Objective: Make suggestions or recommendations in Systemic Mastocytosis based in a panel of Brazilian specialists. Method and results: An online expert panel with 18 multidisciplinary specialists was convened to propose recommendations on the diagnosis and treatment of Systemic Mastocytosis in Brazil. Recommendations were based on discussions of topics and multiple-choice questions and were graded using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence Chart. Conclusion: Twenty-two recommendations or suggestions were proposed based on a literature review and graded according to the findings.

Brazilian chronic myeloid leukemia working group recommendations for discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia in clinical practice

ABSTRACT Introduction: Treatment-free remission (TFR) is a new goal of chronic myeloid leukemia (CML) therapy. TFR is feasible when the patient has achieved a deep and stable molecular response and met the criteria required to ensure its success. Treatment discontinuation should not be proposed to the CML patient if minimum conditions are not met. In Brazil, for example, molecular tests (BCR::ABL1) are not broadly available, making it difficult to monitor the patients adequately. Objective: In this sense, providing TFR recommendations for Brazilian physicians are therefore necessary. These recommendations include the main criteria checklist to start the TKIs treatment discontinuing process in patients diagnosed with CML and the population-eligible characteristics for treatment discontinuation. Method: Age, risk score at diagnosis, TKI treatment duration, BCR::ABL1 transcripts type, depth of the molecular response for treatment discontinuation, treatment adherence, patient monitoring and withdrawal syndrome are essential factors to consider in TFR. After TKI discontinuation, BCR::ABL1 transcripts monitoring should be more frequent. When a major molecular response loss is observed during the monitoring of a patient in TFR, the TKI treatment should be resumed. Conclusion: These recommendations should serve as a basis for medical professionals interested in proposing TKI discontinuation for CML patients in clinical practice. It is important to highlight that, despite the benefits of TFR for the patients and the health system, it should only be feasible following the minimum standards proposed in this recommendation.

Diagnosis and treatment of systemic mastocytosis in Brazil: Recommendations of a multidisciplinary expert panel.

INTRODUCTION: Systemic Mastocytosis comprises a group of neoplastic diseases characterized by clonal expansion and infiltration of mast cells into several organs. The diagnosis and treatment of this disease may be challenging for non-specialists. OBJECTIVE: Make suggestions or recommendations in Systemic Mastocytosis based in a panel of Brazilian specialists. METHOD AND RESULTS: An online expert panel with 18 multidisciplinary specialists was convened to propose recommendations on the diagnosis and treatment of Systemic Mastocytosis in Brazil. Recommendations were based on discussions of topics and multiple-choice questions and were graded using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence Chart. CONCLUSION: Twenty-two recommendations or suggestions were proposed based on a literature review and graded according to the findings.

Brazilian chronic myeloid leukemia working group recommendations for discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia in clinical practice.

INTRODUCTION: Treatment-free remission (TFR) is a new goal of chronic myeloid leukemia (CML) therapy. TFR is feasible when the patient has achieved a deep and stable molecular response and met the criteria required to ensure its success. Treatment discontinuation should not be proposed to the CML patient if minimum conditions are not met. In Brazil, for example, molecular tests (BCR::ABL1) are not broadly available, making it difficult to monitor the patients adequately. OBJECTIVE: In this sense, providing TFR recommendations for Brazilian physicians are therefore necessary. These recommendations include the main criteria checklist to start the TKIs treatment discontinuing process in patients diagnosed with CML and the population-eligible characteristics for treatment discontinuation. METHOD: Age, risk score at diagnosis, TKI treatment duration, BCR::ABL1 transcripts type, depth of the molecular response for treatment discontinuation, treatment adherence, patient monitoring and withdrawal syndrome are essential factors to consider in TFR. After TKI discontinuation, BCR::ABL1 transcripts monitoring should be more frequent. When a major molecular response loss is observed during the monitoring of a patient in TFR, the TKI treatment should be resumed. CONCLUSION: These recommendations should serve as a basis for medical professionals interested in proposing TKI discontinuation for CML patients in clinical practice. It is important to highlight that, despite the benefits of TFR for the patients and the health system, it should only be feasible following the minimum standards proposed in this recommendation.

Mast cell neoplasm: a challenging pathological diagnosis.

Systemic mastocytosis (SM) is a myeloid neoplasm characterized by abnormal growth and accumulation of neoplastic mast cells in at least one extracutaneous site. Clinical presentation and course are variable, most patients are developing an indolent disease and some, an aggressive/leukemic form. Because of its rarity, most physicians are unfamiliar with this disease and do not readily diagnose it. In the present retrospective study, the authors describe 12 patients diagnosed with mast cell neoplasm. Cases were selected from three institutions from Campinas and São Paulo City, Brazil. Morphological features and diagnostic pitfalls are emphasized. Patients' age ranged from 15 to 81 years (mean 51.6 years). Male and female were affected similarly (1:1). Ten patients were classified as aggressive SM, one patient as SM with an associated acute promyelocytic leukemia with t(15;17), and one patient with mast cell sarcoma. The most common clinical findings included anemia (9 patients), thrombocytopenia (3 patients), and skin lesions (3 patients). Bone marrow was involved in 11 patients at diagnosis, followed by skin (5 patients). Five morphological patterns were present: mast cell aggregates (5), plasmacytoid (4), monocytoid (2), spindle cell (2), and epithelioid/pleomorphic (1); two patients showed two histological patterns. In all cases, neoplastic cells were positive for CD117/C-KIT. C-KIT D816V mutation was present in four patients, C-KIT K509I in two, and del(7q22) in one; in five cases no mutational status was available. Despite limited resources, basically morphology and a restricted immunohistochemical panel, it is possible to diagnose mast cell neoplasm. Of note, the pathologist should recognize the different morphological variants of the disease and include adequate markers when requesting immunohistochemical studies.

STMN1 is highly expressed and contributes to clonogenicity in acute promyelocytic leukemia cells.

Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malignancies and involved in proliferation and differentiation. Although a previous study found that the PML-RARα fusion protein, which contributes to the pathophysiology of acute promyelocytic leukemia (APL), positively regulates STMN1 at the transcription and protein activity levels, little is known about the role of STMN1 in APL. In this study, we aimed to investigate the STMN1 expression levels and their associations with laboratory, clinical, and genomic data in APL patients. We also assessed the dynamics of STMN1 expression during myeloid cell differentiation and cell cycle progression, and the cellular effects of STMN1 silencing and pharmacological effects of microtubule-stabilizing drugs on APL cells. We found that STMN1 transcripts were significantly increased in samples from APL patients compared with those of healthy donors (all p < 0.05). However, this had no effect on clinical outcomes. STMN1 expression was associated with proliferation- and metabolism-related gene signatures in APL. Our data confirmed that STMN1 was highly expressed in early hematopoietic progenitors and reduced during cell differentiation, including the ATRA-induced granulocytic differentiation model. STMN1 phosphorylation was predominant in a pool of mitosis-enriched APL cells. In NB4 and NB4-R2 cells, STMN1 knockdown decreased autonomous cell growth (all p < 0.05) but did not impact ATRA-induced apoptosis and differentiation. Finally, treatment with paclitaxel (as a single agent or combined with ATRA) induced microtubule stabilization, resulting in mitotic catastrophe with repercussions for cell viability, even in ATRA-resistant APL cells. This study provides new insights into the STMN1 functions and microtubule dynamics in APL.

Using Antigen Expression of Leukemic Cells for a Fast Screening of Acute Promyelocytic Leukemia by Flow Cytometry.

(1) Background: Acute promyelocytic leukemia is curable, but bleeding complications still provoke a high early mortality. Therefore, a fast diagnosis is needed for timely starting treatment. We developed a diagnostic algorithm using flow cytometric features for discrimination between acute promyelocytic leukemia (APL) and other types of acute myeloid leukemias (AML). (2) Methods: we analyzed newly diagnosed AMLs where immunophenotyping was performed at diagnosis by an 8-color protocol. The mean fluorescence intensity (MFI) of each antigen used was assessed, and those best separating APL from other types of AML were obtained by a discriminant analysis. Phenotypic characteristics of myeloblasts of normal bone marrow were used as controls. (3) Results: 24 cases of APL and 56 cases of other primary AMLs entered the study. Among non-APL AMLs, 4 had fms-related tyrosine kinase 3 gene internal tandem duplications (FLT3-ITD) mutation, 2 had nucleophosmin (NPM1) and 10 had both mutations. SSC (p < 0.0001), HLA-DR (p < 0.0001), CD13 (p = 0.001), CD64 (p = 0.004) and CD33 (p = 0.002) were differentially expressed, but this was not the case for CD34 (50% of non-APLs had a low expression). In the discriminant analysis, the best differentiation was achieved with SSC and HLA-DR discriminating 91.25% of the patients. (4) Conclusion: MFC could differentiate APL from non-APL AML in the majority of the cases.

Challenges in Chronic Myeloid Leukemia Management in South America.

PURPOSE OF REVIEW: Chronic myeloid leukemia (CML) management in developing countries has improved in the last years, but the availability of therapeutic resources, monitoring, reimbursement, and financial issues may be a challenge and interfere with the best practices and results of CML treatment. This review points out the main challenges in CML management in South America. RECENT FINDINGS: In this review, we describe the access to tyrosine kinase inhibitors and monitoring in different countries of South America. We also address the ongoing discontinuation trials, the progress, and limitations of hematopoietic stem cell transplantation in the last years. There are still many challenges for achieving the best outcomes for CML patients in South America. The continuous efforts to provide continuous education, access to tyrosine kinase inhibitors, and monitoring, providing reference centers for CML management and hematopoietic stem cell transplantation may improve patients' outcomes.

Treatment-free remission in patients with chronic myeloid leukemia: recommendations of the LALNET expert panel.

Tyrosine kinase inhibitors (TKIs) have dramatically changed the survival of chronic myeloid leukemia (CML) patients, and treatment-free remission (TFR) has recently emerged as a new goal of CML treatment. The aim of this work was to develop recommendations for TKI discontinuation in Latin America (LA), outside of clinical trials. A working group of CML experts from LA discussed 22 questions regarding TFR and reached a consensus for TFR recommendations in the region. TFR is indicated in patients in first chronic phase, with typical BCR-ABL transcripts, under TKI treatment of a minimum of 5 years, in sustained deep molecular response (DMR; molecular response 4.5 [MR4.5]) for 2 years. Sustained DMR must be demonstrated on at least 4 international reporting scale quantitative polymerase chain reaction (PCR) tests, separated by at least 3 months, in the immediate prior 2 years. After second-line therapy, TFR is indicated in previously intolerant, not resistant, patients. Molecular monitoring is recommended monthly for the first 6 months, every 2 to 3 months from months 7 to 12, and every 3 months during the second year, indefinitely. Treatment should be reintroduced if major molecular response is lost. Monitoring of withdrawal syndrome, glucose levels, and lipid profile is recommended after discontinuation. After TKI reintroduction, molecular monitoring is indicated every 2 to 3 months until MR4.0 achievement; later, every 3 to 6 months. For the TFR attempt, having standardized and reliable BCR-ABL PCR tests is mandatory. These recommendations will be useful for safe discontinuation in daily practice and will benefit patients who wish to stop treatment in emergent regions, in particular, with TKI-related chronic adverse events.

Philadelphia-positive B-lymphoblastic leukemia in a middle-income country - A real-world multicenter cohort.

Outside of clinical trials, few studies have addressed the outcomes of Ph+ acute lymphoblastic leukemia (ALL) in adults, especially from developing world. In this study, we conducted a multicenter analysis on the outcomes of patients aged > 15 years with Ph+ ALL, aiming to get to know an overview of the Brazilian experience as well as to explore baseline factors associated with relapse and mortality in our setting. Over these 10 years, patients were treated with diverse protocols, all of them always combined with a frontline tyrosine-kinase inhibitor. A total of 123 Ph+ ALL patients was included. Imatinib was the first line TKI in 97 %. The complete response rate was 79 %. The early death rate was 15 %, being associated with increasing age at diagnosis (p = 0.06). The use of intensive versus attenuated induction regimen was not associated with higher induction mortality (p = 0.99). Overall, 29 % of patients aged ≤ 60 years underwent allogeneic transplantation, 87 % in first CR. 4-year overall survival (OS) and relapse-free survival were 25 % and 24 %, respectively. The incidence of relapse (death as a competitor) was 29 %, while the non-relapse mortality was 42 %. Only age was independently associated with OS, and lactate dehydrogenase level and central nervous disease at diagnosis were related to relapse in our cohort. This is the first historical cohort multicenter study on Ph+ ALL from Brazil. Reporting these outcomes is essential to encourage public policies to expand access to new drugs and transplantation in middle-income countries.

COVID-19 in chronic myeloid leukemia patients in Latin America.

This observational, multicenter study aimed to report the clinical evolution of COVID-19 in patients with chronic myeloid leukemia in Latin America. A total of 92 patients presented with COVID-19 between March and December 2020, 26% of whom were severe or critical. The median age at COVID-19 diagnosis was 48 years (22-79 years), 32% were 60 years or older, and 61% were male. Thirty-nine patients presented with at least one comorbidity (42.3%). Eighty-one patients recovered (88%), and 11 (11.9%) died from COVID-19. There was one case of reinfection. Patients with a major molecular response presented superior overall survival compared to patients with no major molecular response (91 vs. 61%, respectively; p = 0.004). Patients in treatment-free remission and receiving tyrosine kinase inhibitors showed higher survival rates than patients who underwent hematopoietic stem cell transplantation and those who did not receive tyrosine kinase inhibitors (100, 89, 50, and 33%, respectively; p < 0.001).

Metabolic shift of chronic myeloid leukemia patients under imatinib-pioglitazone regimen and discontinuation.

The Estudo de Descontinuação de Imatinibe após Pioglitazona (EDI-PIO) is a single-center, longitudinal, prospective, phase 2, non-randomized, open, clinical trial (NCT02852486, August 2, 2016 retrospectively registered) for the discontinuation of imatinib after concomitant use of pioglitazone, being the first of its kind in a Brazilian population with chronic myeloid leukemia. Due to remaining of leukemic quiescent cells that are not affected by tyrosine kinase inhibitors, it has been suggested the use of pioglitazone, a PPARγ agonist, together with imatinib as a strategy for the maintenance of deep molecular response. The clinical benefit to this association is still controversial, and the metabolic alteration along this process remains unclear. Therefore, we applied a metabolomic protocol using high-resolution mass spectrometry to profile plasmatic metabolic response of a prospective cohort of ten individuals under discontinuation of imatinib and pioglitazone protocol. By comparing patients under pioglitazone and imatinib treatment with imatinib monotherapy and discontinuation phase, we were able to annotate 41 and 36 metabolites, respectively. The metabolic alterations observed during imatinib-pioglitazone combined therapy are associated with an extensive lipid remodeling, with activation of ß-oxidation pathway, in addition to the presence of markers that suggest mitochondrial dysfunction.

Toll-like receptor gene polymorphisms in patients with myeloproliferative neoplasms.

Toll-like receptors (TLRs) are a family of transmembrane receptors whose signaling control cellular processes of cell proliferation, survival, apoptosis, angiogenesis, remodeling, and repair of tissues. Polymorphisms in TLR genes can change the balance between pro and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation, and cancer. Although many studies have demonstrated the direct involvement of TLR signaling in the benefit of tumor cells in certain cancers, little is known about the influence of these gene polymorphisms on myeloproliferative neoplasms (MPNs). In this context, the objective of the study was to investigate a possible association between the TLR polymorphisms and the development of MPNs. 167 patients diagnosed with MPN and 222 healthy controls from the same region were evaluated. Genomic DNA was extracted and the TLR2 (rs5743708), TLR4 (rs4986790, rs4986791), TLR9 (rs5743836, rs187084) and JAK2V617F polymorphisms were genotyped by PCR-RFLP. The statistical analysis was performed by OpenEpi and SNPstat software. The JAK2V617F mutation was found in 68.32% of patients. TLR9-1486C/T CT genotype was less frequent in patients with polycythemia vera (PV) (OR 0.39, 95% CI 0.20-0.78, P = 0.025). When haplotype frequencies were analyzed, -1237T/-1486C (TLR9) was also less frequent in men (OR 0.58, 95% CI 0.36-0.94) and JAK negative men patients (OR 0.43, 95% CI 0.21-0.88). We can infer that the TLR9-1486 CT genotype could be associated with protection for PV and the TLR9-1237T/-1486C haplotype, protection for men, as well as for JAK negative men patients with MPN. There were no associations between TLR2 and TLR4 gene polymorphisms and MPN.

Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia.

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.