Clinicopathological analysis of follicular lymphoma with BCL2, BCL6, and MYC rearrangements.

Most follicular lymphomas (FL) show t(14;18)/IGH-BCL2 translocation, but rearrangement (R) negative cases exist. A series of 140 FL patients with a BCL2, BCL6, and MYC gene status examined by fluorescence in situ hybridization (FISH) were classified into five groups: (a) BCL2-R group (BCL2-R/BCL6-G/MYC-G) (G, germline), 77 cases; (b) BCL2/BCL6 double-R group (BCL2-R/BCL6-R/MYC-G), 16 cases; (c) BCL6-R group (BCL2-G/BCL6-R/MYC-G), 16 cases; (d) MYC-R group (BCL2-R or G/BCL6-R or G/MYC-R), three cases; (e) Triple-G group (BCL2-G/BCL6-G/MYC-G), 28 cases. The BCL6-R group had different clinicopathological characteristics. It showed lower rates of an advanced clinical stage and bone marrow invasion, less disease progression (p = 0.036), and a 'trend' toward a favorable progression-free survival (PFS) (p = 0.06). It also showed higher rates of grade 3A and MUM1-expression, and when analyzing the interfollicular spread pattern of CD20-positive cells, had fewer cases showing the IF3+ pattern (high interfollicular spread). Moreover, cases with BCL6-R and/or BCL6 gain (with cases of BCL2 rearrangement and/or of copy number gain excluded) correlated with favorable PFS (p = 0.014) and less IF3+ pattern (p = 0.007). We demonstrated that BCL6-R FLs showed unique clinicopathological findings, and FISH of BCL2, BCL6, and MYC is useful for FL diagnosis and clinical management.

Risk factors for lower respiratory tract disease and outcomes in allogeneic hematopoietic stem cell transplantation recipients with influenza virus infection.

INTRODUCTION: Influenza virus infection (IVI) is frequent in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, and reports from several countries indicate high morbidity and mortality from progression to lower respiratory tract disease (LRTD). However, there have been no reports on IVI clinical characteristics, treatment outcomes, and risk factor for progression to LRTD among allo-HSCT recipients in Japan. METHODS: We retrospectively reviewed the medical charts of allo-HSCT recipients who developed IVI between 2012 and 2019. RESULTS: Forty-eight cases of IVI following allo-HSCT were identified at our institution. The median age was 42 years, and median time from allo-HSCT to IVI was 25 months. Thirty-seven patients (77.1%) were administered neuraminidase inhibitors (NAIs) as antiviral therapy within 48 h of symptom onset (early therapy), whereas 11 (22.9%) received NAI over 48 h after onset (delayed therapy). Subsequently, 12 patients (25.0%) developed LRTD after IVI. Multivariate analysis identified older age (hazard ratio [HR], 7.65; 95% confidence interval [CI], 2.22-26.3) and bronchiolitis obliterans (HR, 5.74; 95% CI, 1.57-21.0) as independent risk factors for progression to LRTD. Moreover, land-mark analysis showed that early therapy prevented progression to LRTD (11.8% vs. 45.5%, P = 0.013). The IVI-related mortality rate was 2.1%. CONCLUSIONS: Early NAI treatment is recommended for reducing the risk of LRTD progression due to IVI in allo-HSTC recipients, particularly for older patients and those with bronchiolitis obliterans.

Association between measurable residual disease kinetics and outcomes of Philadelphia chromosome-positive acute lymphoblastic leukemia.

The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) has improved dramatically. Although measurable residual disease (MRD) kinetics during pretransplant treatment has been recently reported to correlate with patient outcomes, it is unclear whether prognosis is better if the MRD falls below the detection sensitivity soon after induction therapy. We retrospectively analyzed data of 37 Ph + ALL patients who were treated with autologous or allogeneic stem cell transplantation (auto-SCT, allo-SCT) at our institute from 2003 to 2019. Based on MRD kinetics, patients were divided into three groups: early responders (MRD became negative after induction therapy [n = 10, 27.0%]); late responders (MRD remained positive after induction therapy and became negative just before SCT [n = 12, 32.4%]); and poor responders (MRD was positive until just before SCT [n = 15, 40.5%]). The 5-year disease-free survival (DFS) rates for the three groups were 80.0%, 60.0%, and 29.9%, respectively (P = 0.037). The 5-year overall survival rates were not significantly different. The 5-year relapse rates were 0.0%, 31.7%, and 49.5%, respectively (P = 0.045). Non-relapse mortality (NRM) rates were similar among the three groups. Subgroup analysis for the cases that received posttransplantation tyrosine kinase inhibitor maintenance therapy revealed that DFS was similarly dependent on MRD kinetics (P = 0.022). This study clarified that MRD kinetics was a significant prognosticator for DFS and relapse rate in Ph + ALL.

Clinical outcome of Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly in the rituximab era.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma. The incidence of Epstein-Barr virus (EBV)-positive DLBCL in Asian and Latin American countries ranges from 8 to 10%. The prognosis of patients with EBV-positive DLBCL is controversial. To compare the clinical outcome of EBV-positive and EBV-negative patients with DLBCL in the rituximab era, we analyzed 239 patients with de novo DLBCL diagnosed between January 2007 and December 2011. The presence of EBV in lymphoma cells was detected using EBV-encoded RNA in situ hybridization, and it was found that 18 (6.9%) of 260 patients with diagnosed DLBCL tested positive. Among the 260 cases, 216 cases were treated with rituximab plus chemotherapy, as were 8 EBV-positive DLBCL patients. The median overall survival and progression-free survival times in patients with EBV-positive DLBCL were 8.7 months and 6.8 months, respectively. The median overall survival and progression-free survival could not be determined in EBV-negative DLBCL patients (P = 0.0002, P < 0.0001, respectively). The outcome of patients with EBV-positive DLBCL remains poor, even in the rituximab era.

Aplastic Anemia with Epstein-Barr Virus Reactivation after Anti-thymocyte Globulin Therapy.

Lymphoproliferative disorders and Epstein-Barr virus reactivation (EBV-LPDs) have various forms of onset, ranging from infectious mononucleosis-like syndrome (IM-like) to lymphoma, although whether or not IM-like progresses to lymphoma remains unclear. A 61-year-old man was diagnosed with aplastic anemia (AA). Polyclonal atypical B-lymphocytes were observed in the peripheral blood, and IM-like was diagnosed. Atypical lymphocytes disappeared, but a gastrointestinal examination revealed diffuse large B-cell lymphoma (DLBCL). Rituximab was initiated but later discontinued because of severe acute respiratory syndrome coronavirus 2 infection. Pancytopenia due to AA exacerbation recurred. The patient ultimately died of multiple organ failure due to bacterial infection.

Fetal hemoglobin level predicts lower-risk myelodysplastic syndrome.

The relationship between fetal hemoglobin (HbF) levels and disease prognosis in patients with myelodysplastic syndrome (MDS) is unclear. This study aimed to clarify the relationship between HbF level and the prognosis of MDS. To this end, data from 217 patients diagnosed with MDS between April 2006 and August 2020 at Ebina General Hospital were analyzed retrospectively. The primary endpoint was leukemia-free survival (LFS) for 5 years after diagnosis. HbF levels were significantly higher in patients with MDS than in control patients without MDS (n = 155), with a cut-off value of 0.4%. Higher-risk patients had a similar prognosis regardless of HbF level, but lower-risk patients had longer LFS at intermediate HbF levels. Although prognosis based on pre-treatment HbF levels did not differ significantly among azacitidine-treated patients, prognosis tended to be better in lower-risk patients with intermediate HbF levels. Multivariate analysis showed that the intermediate HbF category correlated with LFS, independently of MDS lower-risk prognostic scoring system (LR-PSS)-related factors. This study is the first to assess the association between HbF levels and the new World Health Organization 2016 criteria for MDS, demonstrating the significance of HbF levels in the prognosis of MDS.

Impact of previous anthracycline therapy in patients with acute myeloid leukemia receiving venetoclax.

Venetoclax (VEN) combination regimens are now recognized as effective against acute myeloid leukemia (AML). However, the prognosis of patients who do not attain a composite complete response (cCR) is extremely poor, and clinical determinants of response remain unknown. Medical records of 57 patients with AML treated with VEN combination regimens from April 2021 to March 2022 at six institutions were retrospectively analyzed. The primary endpoint was cCR, complete remission, or complete remission with incomplete hematologic recovery after one cycle of VEN combination regimen. Five patients had previously relapsed after allogeneic hematopoietic stem cell transplantation (allo-SCT). The treatment regimen was azacitidine-VEN in 48 patients (84%) and low-dose cytarabine-VEN in 9 patients (16%). Thirty patients (53%) achieved cCR after one cycle of a VEN regimen. In univariate analysis, the number of prior chemotherapy regimens, post-allo-SCT relapse, and cytogenetic risk category were associated with a decreased likelihood of achieving cCR. In multivariate analysis, second-line chemotherapy remained a significant predictor of response. Patients who received anthracycline immediately before the VEN regimen had a higher cCR rate than patients who did not receive anthracycline. In this study, prior chemotherapy/allo-SCT and cytogenetic risk were associated with VEN treatment outcomes.

Association of CDKN2A/2B deletion with relapse after hematopoietic stem cell transplantation for acute lymphoblastic leukemia.

The most important prognostic factor for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is minimal residual disease (MRD). Previous studies have reported copy number variants of genes such as IKZF1, CDKN2A/2B, and PAX5. These gene mutations can be analyzed using multiplex ligation-dependent probe amplification (MLPA), which is less costly and easier to perform than large-scale gene mutation analyses. In this study, we performed copy number variant analysis of leukemia cells at the first onset of Ph+ALL in a case series of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using the MLPA method. We analyzed how it influenced allo-HSCT prognosis together with MRD information. CDKN2A/2B copy number variations significantly increased the rate of post-transplant recurrence (P=0.025) and significantly reduced disease-free survival (P=0.015). Additionally, patients with IKZF1 deletions had a significantly higher post-transplant recurrence rate (P=0.042). Although they were positive for pre-transplant MRD, no relapse was observed in patients with wild-type copy number variations in IKZF1 or CDKN2A/2B. CDKN2A/2B copy number variation is a crucial factor that can be confirmed at initial onset as a post-transplant prognostic factor of Ph+ALL.

The Effect of Roxadustat on Transfusion-Dependent Myelodysplastic Syndrome Complicated by Chronic Kidney Disease.

Haematopoietic insufficiency is the treatment target of lower-risk myelodysplastic syndrome (MDS). Although erythropoiesis-stimulating agents (ESAs) are generally effective for treating anaemia, resistance can develop. Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) improves renal anaemia by promoting endogenous erythropoietin production and normalizing iron metabolism. HIF-PH inhibitors could be used to treat MDS, but their efficacy and safety have not been studied. A 78-year-old female patient with essential thrombocythemia gradually developed anaemia and was diagnosed with therapy-related MDS 4 years later. The anaemia temporarily improved with ESAs, but the patient became transfusion dependent. At the same time, anaemia and chronic renal failure due to nephrosclerosis progressed, and the patient was diagnosed with MDS with renal anaemia. After switching from ESAs to roxadustat, an HIF-PH inhibitor, anaemia improved, and the patient was no longer transfusion dependent. No progression of the underlying disease or any adverse events was observed 4 months after initiating roxadustat.

A case of JAK2V617F-positive essential thrombocythemia where allele burden was reduced by a PD-1 inhibitor.

The Janus kinase/signal transducers and activators of transcription signaling pathway induces programmed death ligand-1 (PD-L1) expression. JAK2 mutation at position 617 (JAK2V617) is a frequent driver of myeloproliferative neoplasms (MPN) through PD-L1 expression. Although PD-1 inhibitors should be effective against MPN with JAK2V617F mutation, this has not yet been reported in humans. Thus, we assessed the efficacy of a PD-1 inhibitor in a lung cancer patient with JAK2V617F-positive essential thrombocythemia (ET). A 71-year-old man was diagnosed with ET, and with lung carcinoma 3 years later. After right lobectomy and postoperative chemotherapy, pembrolizumab [a PD-1 inhibitor (200 mg, every 3 weeks)] was initiated for refractory lung carcinoma. Lung cancer progression did not occur for 1.5 years under treatment. Most megakaryocytes were PD-L1-positive, and after pembrolizumab initiation, platelet count remained below 45 × 104/µL without the need for other cytoreductive therapies for ET. The JAK2V617F allele burden gradually decreased from 11.5% at diagnosis to 2.9% after 17 months of pembrolizumab treatment. Other peripheral blood lineages did not decrease, and pembrolizumab treatment was continued without any adverse events. This is the first report demonstrating the effectiveness of pembrolizumab in an MPN patient with JAK2V617F mutation.

The Role of Hypertension and Renin-angiotensin-aldosterone System Inhibitors in Bleomycin-induced Lung Injury.

INTRODUCTION: The risk factors for bleomycin-induced lung injury (BLI), a fatal complication of cancer chemotherapy, are not well-established. The renin-angiotensin-aldosterone system (RAAS) has recently been suggested to play a role in the development of lung injury. This study clarified the impact of hypertension (HTN) and the administration of RAAS inhibitors on BLI occurrence in patients treated with bleomycin-containing regimens. PATIENTS AND METHODS: We retrospectively analyzed the data of 190 patients treated with a bleomycin-containing regimen for Hodgkin lymphoma or germ cell tumors at our institutions from 2004 to 2018. RESULTS: Overall, 190 patients received bleomycin, and symptomatic BLI occurred in 21 (11.1%) cases. In the multivariate analysis, age ≥ 65 years (odd ratio, 10.90; 95% confidence interval, 3.72-32.20; P < .001) and history of HTN (odds ratio, 3.32; 95% confidence interval, 1.07-10.30; P = .04) were found to be significant risk factors for BLI onset. BLI occurred in 3.6% (n = 5) of patients with no risk, 11.8% (n = 2) of those whose only risk factor was HTN, 31.6% (n = 6) of those whose only risk factor was age ≥ 65 years, and 57.1% (n = 8) of those with both risk factors (P < .001). BLI-induced mortality rates in each group were 0.0% (n = 0), 5.9% (n = 1), 10.5% (n = 2), and 42.9% (n = 6) (P < .001), respectively. Among 31 patients with HTN, BLI incidence was 12.5% in patients who were administered RAAS inhibitors and 53.3% in those who were not (P = .02). CONCLUSION: Older age and history of HTN were independent risk factors for the development of BLI, and the administration of RAAS inhibitors might reduce the onset of BLI.

Clinicopathological evaluation of methotrexate-associated lymphoproliferative disorders with special focus on Epstein-Barr virus-positive mucocutaneous lesions.

Some patients diagnosed with methotrexate-associated lymphoproliferative disorder (MTX-LPD) develop spontaneous regression upon the discontinuation of MTX, whereas others require chemotherapy. The mechanisms underlying this differential response and the capacity to spontaneously regress are not clearly understood. We evaluated numerous clinicopathological features in 63 patients diagnosed with MTX-LPD, with a special focus on those with Epstein-Barr virus (EBV)-positive mucocutaneous lesions (EBVMCL). The diagnosis of EBVMCL included cases of both EBV-positive mucocutaneous ulcers (EBVMCU) and diffuse gingival swelling associated with proliferation of EBV-positive large B-cells. Of the four subgroups of MTX-LPD, one-year treatment-free survival (TFS) after the discontinuation of MTX was achieved among those with EBVMCL (100%), diffuse large B-cell lymphoma (57%), Hodgkin-like lesions (60%), or classical Hodgkin lymphoma (29%); a significant difference in TFS was observed when comparing the responses of patients with EBVMCL to the those diagnosed with other subtypes. Multivariate analysis revealed predictive factors for prolonged TFS that included EBV-positive lesions and comparatively low levels of serum LDH. Taken together, our study suggests that a diagnosis of EBVMCL is related to the overall clinical outcome after the discontinuation of MTX.

A Case of Composite Lymphoma with Extranodal NK/T-cell Lymphoma, Nasal-type and Diffuse Large B-cell Lymphoma.

Composite lymphoma (CL) is defined as the occurrence of two distinct types of lymphoma within the same patient. Most cases of CL involve Hodgkin and non-Hodgkin lymphomas or two distinct types of B-cell lymphomas; true CL is a composite B-cell and T-cell lymphoma, and is rare. We herein report a case involving concurrent extranodal NK/T-cell lymphoma, nasal-type and diffuse large B-cell lymphoma, which has not been previously reported. As the mechanisms and treatments of composite B-cell and T-cell lymphomas are unclear, further studies are required to improve the prognosis.

T-448, a specific inhibitor of LSD1 enzyme activity, improves learning function without causing thrombocytopenia in mice.

Dysregulation of histone H3 lysine 4 (H3K4) methylation has been implicated in the pathogenesis of several neurodevelopmental disorders. Targeting lysine-specific demethylase 1 (LSD1), an H3K4 demethylase, is therefore a promising approach to treat these disorders. However, LSD1 forms complexes with cofactors including growth factor independent 1B (GFI1B), a critical regulator of hematopoietic differentiation. Known tranylcypromine-based irreversible LSD1 inhibitors bind to coenzyme flavin adenine dinucleotide (FAD) and disrupt the LSD1-GFI1B complex, which is associated with hematotoxicity such as thrombocytopenia, representing a major hurdle in the development of LSD1 inhibitors as therapeutic agents. To discover LSD1 inhibitors with potent epigenetic modulation and lower risk of hematotoxicity, we screened small molecules that enhance H3K4 methylation by the inhibition of LSD1 enzyme activity in primary cultured rat neurons but have little impact on LSD1-GFI1B complex in human TF-1a erythroblasts. Here we report the discovery of a specific inhibitor of LSD1 enzyme activity, T-448 (3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide fumarate). T-448 has minimal impact on the LSD1-GFI1B complex and a superior hematological safety profile in mice via the generation of a compact formyl-FAD adduct. T-448 increased brain H3K4 methylation and partially restored learning function in mice with NMDA receptor hypofunction. T-448-type LSD1 inhibitors with improved safety profiles may provide unique therapeutic approaches for central nervous system disorders associated with epigenetic dysregulation.

Pulmonary phagocyte-derived NPY controls the pathology of severe influenza virus infection.

Crosstalk between the autonomic nervous system and the immune system by means of the sympathetic and parasympathetic pathways is a critical process in host defence. Activation of the sympathetic nervous system results in the release of catecholamines as well as neuropeptide Y (NPY). Here, we investigated whether phagocytes are capable of the de novo production of NPY, as has been described for catecholamines. We show that the synthesis of NPY and its Y1 receptor (Y1R) is increased in phagocytes in lungs following severe influenza virus infection. The genetic deletion of Npy or Y1r specifically in phagocytes greatly improves the pathology of severe influenza virus infection, which is characterized by excessive virus replication and pulmonary inflammation. Mechanistically, it is the induction of suppressor of cytokine signalling 3 (SOCS3) via NPY-Y1R activation that is responsible for impaired antiviral response and promoting pro-inflammatory cytokine production, thereby enhancing the pathology of influenza virus infection. Thus, direct regulation of the NPY-Y1R-SOCS3 pathway on phagocytes may act as a fine-tuner of an innate immune response to virus infection, which could be a therapeutic target for lethal influenza virus infection.

Effect of damage type on stimulation of human excision nuclease by SWI/SNF chromatin remodeling factor.

To investigate the repair of different types of DNA lesions in chromatin, we prepared mononucleosomes containing an acetylaminofluorene-guanine adduct (AAF-G), a (6-4) photoproduct, or a cyclobutane pyrimidine dimer (CPD) and measured the repair of these lesions by reconstituted 6-factor human excision nuclease. We find that incorporation into nucleosomes inhibits the repair of CPD more severely than repair of the AAF-G adduct and the (6-4) photoproduct. Equally important, we find that SWI/SNF stimulates the removal of AAF-G and (6-4) photoproduct but not of CPD from nucleosomal DNA. These results shed new light on the low rate of repair of CPDs in human cells in vivo.

The SWI/SNF chromatin-remodeling factor stimulates repair by human excision nuclease in the mononucleosome core particle.

To investigate the role of chromatin remodeling in nucleotide excision repair, we prepared mononucleosomes with a 200-bp duplex containing an acetylaminofluorene-guanine (AAF-G) adduct at a single site. DNase I footprinting revealed a well-phased nucleosome structure with the AAF-G adduct near the center of twofold symmetry of the nucleosome core. This mononucleosome substrate was used to examine the effect of the SWI/SNF remodeling complex on the activity of human excision nuclease reconstituted from six purified excision repair factors. We found that the three repair factors implicated in damage recognition, RPA, XPA, and XPC, stimulate the remodeling activity of SWI/SNF, which in turn stimulates the removal of the AAF-G adduct from the nucleosome core by the excision nuclease. This is the first demonstration of the stimulation of nucleotide excision repair of a lesion in the nucleosome core by a chromatin-remodeling factor and contrasts with the ACF remodeling factor, which stimulates the removal of lesions from internucleosomal linker regions but not from the nucleosome core.

Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation.

Previous studies have reported that an antibody that blocks programmed cell death 1 (PD-1) has therapeutic activity in patients with refractory/relapsed Hodgkin lymphoma (HL). However, the safety and efficacy of these agents in the post-allogeneic stem cell transplantation (allo-SCT) setting are not well known. Here, we describe a patient who was diagnosed as classical HL and treated with five regimens of chemotherapies with autologous SCT. Complete remission (CR) was not achieved following this initial treatment, so we performed allo-SCT from an HLA-matched sibling donor. Since his disease progressed at day 403 after allo-SCT, we decided to use nivolumab in the treatment of his refractory disease. To prevent the worsening of his chronic graft-versus-host disease (GVHD), we reduced the initial dose and frequency of nivolumab compared with the previous report. After four courses of 0.5 mg/kg of nivolumab every three weeks, FDG-PET imaging showed partial response (PR) to the treatment, a remarkable result. However, since the escalated dose of 2 mg/kg resulted in worsening of dyspnea and skin sclerosis, we initiated systemic administration of prednisolone and reduced nivolumab to 1 mg/kg. At the time of this report, his HL is in stable PR with three weekly administration of nivolumab and steroid controlled mild chronic GVHD.

NKG2D gene polymorphisms are associated with disease control of chronic myeloid leukemia by dasatinib.

A recent study reported that treatment-free remission (TFR) of chronic myeloid leukemia (CML) after dasatinib (Das) treatment was significantly associated with natural killer (NK) cell proliferation in the peripheral blood. However, biomarkers to predict lymphocytosis or successful TFR are not well characterized. In order to clarify individual differences in NK cell responses among patients treated with Das, we retrospectively analyzed the association between polymorphisms in the natural killer group 2D receptor [NKG2D; also known as killer cell lectin like receptor K1 (KLRK1)] gene and clinical outcomes in 31 patients treated with Das as first-line treatment for CML. Patients with the NKG2D HNK1/HNK1 (high-cytotoxic activity-related allele on NKG2D hb-1) haplotype achieved MR4.5 more quickly than those with other haplotypes [hazard ratio (HR) 4.39; 95% confidence interval (CI) 2.75-118.6; P = 0.004]. In addition, NK cells with the NKG2D HNK1 allele exhibited enhanced phosphorylation of vav guanine nucleotide exchange factor 1 (VAV1) at Tyr174. These data suggest that NKG2D gene polymorphisms may represent candidate biomarkers for the prediction of TFR following Das treatment.

A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells.

Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here, we describe the antileukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroid leukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound. T-3775440 treatment enforced transdifferentiation of erythroid/megakaryocytic lineages into granulomonocytic-like lineage cells. Mechanistically, T-3775440 disrupted the interaction between LSD1 and growth factor-independent 1B (GFI1B), a transcription factor critical for the differentiation processes of erythroid and megakaryocytic lineage cells. Knockdown of LSD1 and GFI1B recapitulated T-3775440-induced transdifferentiation and cell growth suppression, highlighting the significance of LSD1-GFI1B axis inhibition with regard to the anti-AML effects of T-3775440. Moreover, T-3775440 exhibited significant antitumor efficacy in AEL and AMKL xenograft models. Our findings provide a rationale for evaluating LSD1 inhibitors as potential treatments and indicate a novel mechanism of action against AML, particularly AEL and AMKL. Mol Cancer Ther; 16(2); 273-84. ©2016 AACR.