Pure Erythroid Leukemia Research Articles

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia.

This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369.

Abstract 2021: Wilms tumor and pure erythroid leukemia arising from the same clone in an adolescent

Abstract Wilms tumor and pure erythroid leukemia (PEL) are distinct malignancies arising from different tissues. Here we describe a case of an adolescent with a constitutional pathogenic BRCA2 variant who was diagnosed with a Wilms tumor and developed PEL while undergoing treatment. We provide evidence that both malignancies are distinct and arose from the same clone. A 16-year-old boy presented with a diffusely anaplastic Wilms tumor metastatic to liver. He was treated with radical nephrectomy, partial hepatectomy, radiation, and multiagent chemotherapy. Six months into treatment he developed new lung and liver lesions along with cytopenias. A bone marrow aspirate confirmed a diagnosis of PEL. His disease progressed after one cycle of myeloid leukemia-directed chemotherapy and he died of disease shortly after. Samples from his initial renal tumor, blood at Wilms tumor diagnosis, and diagnostic bone marrow for PEL were characterized by whole genome sequencing and RNA sequencing. Two sequence variants were shared in both tumors but were not found in the constitutional tissue (blood at first presentation): a promoter variant in TERT (c.-124C>T) and a missense variant in PDE4DIP (p.Gln1045His). Although neither variant has been reported in Wilms tumor or PEL, the TERT variant has been well described in other tumor types and is associated with decreased survival in some carcinomas. Both tumors also had pathogenic TP53 variants albeit a different one in each tumor (p.Arg175His in the Wilms tumor, p.Asp228* in PEL). Loss of heterozygosity at TP53 was present in both malignancies via copy number loss of 17p with a shared breakpoint. Furthermore, while both malignancies had complex and distinct karyotypes, 7p loss and 22q loss with identical breakpoints were present in both. None of these variants or copy number variants were present in constitutional tissue. RNA sequencing data confirmed the histologic finding that these were distinct malignancies as the expression patterns for each malignancy were consistent with previously published expression data for Wilms tumors and myeloid leukemias respectively. Although the patient had a constitutional pathogenic BRCA2 variant, loss of heterozygosity at that locus was not found in either tumor. Chromosome fragility testing for Fanconi anemia was uninterpretable due to the concomitant use of chemotherapeutic agents at the time of testing, however the patient had no phenotypic features to support this diagnosis. In this case there are multiple lines of evidence suggesting that a Wilms tumor and PEL arose from the same clone including shared TERT variants and copy number variant breakpoints. Kidney and hematopoietic tissue both arise from the embryonic mesoderm suggesting that the earliest alterations occurred in this tissue. The contribution of each shared pathogenic variant (TERT, BRCA2, 17p loss) to tumorigenesis and the role of chemotherapy in PEL development are still under investigation. Citation Format: Anita Villani, Winnie Lo, Yisu Li, Mohamed Abdelhaleem, Mary Shago, Federico Comitani, My Linh Thibodeau, Sarah Alexander, Uri Tabori, David Malkin, Adam Shlien, Jack Brzezinski. Wilms tumor and pure erythroid leukemia arising from the same clone in an adolescent [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 2021.

Differential characteristics of TP53 alterations in pure erythroid leukemia arising after exposure to cytotoxic therapy

Pure erythroid leukemia (PEL) is a rare acute leukemia with a dismal prognosis. TP53 mutations are a dominant feature of PEL, but the characteristics of TP53 alterations in PEL without prior exposure to cytotoxic therapy (d-PEL) or with such exposure (t-PEL) is unknown. We studied 25 patients with TP53-mutated PEL including 16 d-PEL and 9t-PEL. Both groups had comparable clinical findings and overall survival. The TP53 mutation, commonly missense, was present in the dominant clone in all cases. In the d-PEL group, 10/16 (62.5%) had one TP53 mutation compared to 8/9 (89%) patients in the t-PEL group. In the d-PEL group, 9/16 (56.2%) patients had hotspot mutations compared to 2 (22.2%) patients in the t-PEL group. Notably, monosomy 17 or del(17p) were less common in the d-PEL group (26.6%) compared to the t-PEL group (71.4%), underscoring distinctive TP53 alterations in d-PEL versus t-PEL, possibly reflecting different fitness advantages.

Pure erythroid leukemia is characterized by biallelic TP53 inactivation and abnormal p53 expression patterns in de novo and secondary cases.

Not available.

TYRO3 Knockdown Suppresses the Growth of Myeloid Leukaemia Cells.

TYRO3 is a member of the TAM family (TYRO3, AXL, and MERTK) of receptor tyrosine kinases. While the roles of activated AXL and MERTK in the growth of leukaemia cells have been reported, the effect of TYRO3 has not been determined. Therefore, we examined the effects of TYRO3 knockdown on the growth of leukaemia cell lines. Three human leukaemia cell lines (AA derived from pure erythroid leukaemia, OCI/AML2, and K562), which express TYRO3 protein were used in this study. To induce TYRO3 knockdown, small interfering RNA (siRNA) against TYRO3 was transfected using an electroporation system. Cell growth was assessed by a colorimetric assay. The expression levels and activation of various signalling proteins were examined by immunoblotting. Changes in comprehensive gene expression after TYRO3 knockdown were examined by microarray analysis. TYRO3 knockdown suppressed cell growth in the leukaemia cell lines tested. Additionally, the knockdown suppressed phosphorylation of signal transducer and activator of transcription-3 in AA cells, and extracellular signal-regulated kinase (ERK) 1/2 in AA and OCI/AML2 cells; both are downstream molecules of TYRO3 signalling. TYRO3 knockdown also suppressed the expression of survivin in all the cell lines. TYRO3 knockdown potently suppressed TYRO3 mRNA expression but not that of AXL and MERTK. Furthermore, TYRO3 knockdown suppressed cyclin D1 mRNA expression, which is a downstream molecule of ERK. TYRO3 plays a role in leukaemia cell growth and is a potential therapeutic target for leukaemia.

GLUT1 Immunohistochemistry Is a Highly Sensitive and Relatively Specific Marker for Erythroid Lineage in Benign and Malignant Hematopoietic Tissues.

Glucose transporter 1 (GLUT1), a glucose transporter, is an abundant protein in erythrocytes with expression beginning early in erythropoiesis. We sought to evaluate the utility of GLUT1 immunohistochemistry (IHC) as a diagnostic marker for identifying erythroid differentiation in hematopoietic tissues, including neoplastic erythroid proliferations. A variety of benign and neoplastic bone marrow biopsy specimens containing variable proportions of erythroid precursors were selected (n = 46, including 36 cases of leukemia). GLUT1 IHC was performed using a commercially available polyclonal antibody. Each case was evaluated for staining of erythroid precursors, nonerythroid hematopoietic cells, and blasts. A GATA1/GLUT1 double stain was performed on one case to confirm coexpression of GLUT1 on early erythroid precursors. Staining was compared with other erythroid markers, including glycophorin C. GLUT1 demonstrated strong membranous staining in erythroid precursors of all cases, which was restricted largely to the erythroid lineage. Of the 36 leukemia cases, all 6 cases of pure erythroid leukemia and both cases of therapy-related acute myeloid leukemia with erythroid differentiation showed positive GLUT1 staining in blasts. Otherwise, only lymphoblasts in B-lymphoblastic leukemia showed weak to moderate granular cytoplasmic staining (four of five cases). GLUT1 IHC is a highly sensitive and relatively specific marker for erythroid lineage in benign and neoplastic bone marrow biopsy specimens.

Pure Erythroid Leukaemia- Report of An Extremely Rare Case with Dismal Prognosis

Pure erythroid leukaemia (PEL) is a rare and aggressive form of acute leukaemia whose biology remains poorly characterized. The category of acute erythroid leukaemia was signiûcantly revised in the 2016 revision to the World Health Organization (WHO) classiûcation of myeloid neoplasms. In the previous 2008 WHO classiûcation, acute erythroid leukaemia was categorized into two subtypes: erythroleukaemia and pure erythroid leukaemia (PEL), whereas in the 2016 WHO update, erythroleukaemia was merged into myelodysplastic syndrome and PEL becomes the only type of acute erythroid leukaemia. De novo pure erythroid leukaemia is a disease of adults (median age 68 years), exhibits a striking male predominance, is universally associated with an abnormal karyotype and has an exceedingly poor overall median survival of 1.4 months. Given the limited number of reports of this rare and diagnostically challenging entity, we report clinicopathologic characteristics of a case of PEL, diagnosis was made by the bone marrow morphology and immunophenotyping. J Bangladesh Coll Phys Surg 2021; 39: 266-268

Acute Erythroleukemia in a Trauma Patient. A Case Report.

Introduction: Acute erythroid leukemia (AEL) is a rare type of acute myeloblastic leukemia. Acute erythroid leukemia is characterized by a predominant erythroid proliferation, there are 2 subtypes: erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia…
 Myelodysplastic syndromes (MDS) are a group of biologically and clinically heterogeneous clonal disorders characterized by ineffective hematopoiesis and peripheral cytopenia due to high apoptosis
 The purpose to presenting this case is how to differentiate an acute erythroleukemia (AEL) from myelodysplastic syndrome (MDS).
 Case report. A 74-year-old man came to emergency room after he falling down from the stairs and then was hospitalized with a two weeks history of severe weakness, anorexia, weight loss. He suffered of diabetes mellitus type II insulin dependent, and HTA. The physical examination showed cutaneous and conjunctival pallor, large ecchymosis in the low extremities and hepatosplenomegaly. CBC showed: pancytopenia and macrocytosis, neutrophils 60%, normoblasts 4:100 and reticulocyte count 3%.
 Conclusions: The diagnosis was Acute Erythroid Leukemia. The % of myeloblasts in bone marrow was > 20% of non-erythroid cells. Erythroleukemia characterizes from hepatomegaly this is found and in our case. Differential diagnosis is based mainly in bone marrow aspiration, immunophenotyping (flow cytometry).

P53 immunohistochemistry discriminates between pure erythroid leukemia and reactive erythroid hyperplasia

Pure erythroid leukemia (PEL) is a rare, aggressive subtype of acute myeloid leukemia with a poor prognosis. The diagnosis of PEL is often medically urgent, quite challenging, and is typically a diagnosis of exclusion requiring meticulous distinction from non-neoplastic erythroid proliferations, particularly florid erythroid hyperplasia/regeneration. Given the frequency of TP53 mutations in the molecular signature of PEL, we hypothesize that differential p53 expression by immunohistochemistry (IHC) may be useful in distinguishing PEL versus non-neoplastic erythroid conditions. We performed p53 IHC on 5 normal bone marrow, 46 reactive erythroid proliferations, and 27 PEL cases. We assessed the positivity and intensity of nuclear staining in pronormoblasts and basophilic normoblasts using a 0–3+ scale with 0 being absent (with internal positive controls) and 3 being strong nuclear positivity. A total of 26/27 PEL cases showed strong, uniform, diffuse intense staining by the neoplastic pronormoblasts versus 0/5 and 0/46 normal and reactive controls, respectively. The control cases show various staining patterns ranging from 0 to 3+ in scattered erythroid precursor cells. Uniform, strong p53 positivity is unique to PEL and discriminates this entity from a benign erythroid mimic. Thus, p53 IHC may be a useful marker in urgent medical cases to assist in the confirmation of a malignant PEL diagnosis while awaiting the results of additional ancillary studies such as cytogenetics.

Erythroblastic sarcoma transformation from a chronic myeloid neoplasm with FGFR1 rearrangement presenting as a pleural effusion: a case report

Myeloid/lymphoid neoplasms with FGFR1 rearrangement (MLN-FGFR1) comprise a heterogeneous group of neoplasms that can present as a myeloproliferative neoplasm, a myelodysplastic/myeloproliferative neoplasm, acute myeloid leukemia, T or B lymphoblastic leukemia/lymphoma, or mixed phenotype acute leukemia. The overall outcome of these neoplasms is poor, and these patients often show cytogenetic evolution with gain of additional chromosomal abnormalities leading to transformation to acute leukemia. Pure erythroid leukemia and erythroblastic sarcoma evolving from a preexisting chronic myeloid neoplasm have rarely been described; however, this has not been reported in MLN-FGFR1. Herein we describe a biopsy-proven chronic myeloid neoplasm with FGFR1 rearrangement with transformation to erythroblastic sarcoma presenting as a pleural effusion.

Pure erythroid leukemia.

The diagnosis of pure erythroid leukemia (PEL) can be challenging. Prompt identification of CD45+, CD34‐, CD71+, CD117+, and E‐cadherin+ erythroblasts is important. The differential diagnosis is broad and includes megaloblastic anemia.

Pure erythroid leukemia.

Pure erythroid leukemia is a rare and aggressive form of acute leukemia with a deleterious clinical course. It is of erythroid lineage without myeloblastic component, representing >80% of marrow cellularity, with ≥30% proerythroblasts.

Therapy-Related Pure Erythroid Leukaemia with Complex Karyotype Following Successful Treatment for Acute Promyelocytic Leukaemia

Therapy-Related Pure Erythroid Leukaemia with Complex Karyotype Following Successful Treatment for Acute Promyelocytic Leukaemia

Pure erythroid leukemia transformed from myelodysplastic syndrome: a case report

纯红系白血病是一种少见类型的急性白血病，老年发病多见，临床进展较快，中位生存期短，预后差。本研究中，我们分析1例骨髓增生异常综合征(MDS)转化纯红系白血病临床表现、治疗经过及临床诊断，并结合2016年世界卫生组织对造血和淋巴组织肿瘤分类关于红白血病的修订进行文献复习。

Bone marrow necrosis after umbilical cord blood transplantation in a patient with pure erythroid leukemia

Bone marrow necrosis after umbilical cord blood transplantation in a patient with pure erythroid leukemia

Pure erythroid leukemia, presenting with pancytopenia. Images in Hematology.

Pure erythroid leukemia is an aggressive form of acute leukemia, presenting with pancytopenia. It is defined as a neoplasm of erythroid lineage without a significant myeloblastic component, representing >80% of marrow, with 30% or more proerythroblasts. The disease has a rapid clinical course with median survival of only 3 months.

PB1765 CHARACTERISTICS OF ERYTHROLEUKEMIA ABOUT 10 CASES WITH REVIEW OF THE LITERATURE

Background:Acute erythroblastic leukemia (AML‐M6) is a rare entity, accounting for 3‐4% of all LAs. There are two types: erythroleukemia and pure erythroid leukemia. It is most often manifested by signs of cytopenia and infiltration of extrahematopoietic tissues, and is more common in adults than in children with a poor prognosis.Aims:The objective of this study is to describe the clinical, biological and evolutionary aspects of erytholeukemia in a monocentric retrospective study.Methods:the diagnosis is based on a cytological examination of the blood smear (FS) and medullary (PMO) as well as the immunophenotypic examination. We calculated overall survival by Kaplan Meier methodResults:n = 181 (evaluable), n = 10 patients with AML6 according to the FAB classification (5%). • The cytological study of FS and PMO + CMF results led to the diagnosis of erythroleukemia in 08 of our patients and pure erythroid leukemia in 2 patients. Mean age = 47 ± 21.77 years [0‐64]. Sex ratio = 1.5 (6H / 4F). Duration: 40 ± 35 days [01‐90]. Symptoms of bone marrow failure: PCM (100%), hemorrhagic syndrome: 3 cases (30%), infection: 04 cases (40%), splenomegaly: 04 cases (30%), mean WB = 84,300 ± 11.260 giga / l [125.000‐83.400], peripheral blast level (avg = 26 ± 23% [1‐65]), medullary blasts = average 49.5 ± 19% (08‐93) • mean hemoglobin level = 8.06 ± 1.09 g / dl [5‐10], platelets: 21‐151giga / l (avg: 65,900 ± 47,450 / mm3) n = 03 patients had severe thrombocytopenia at 13‐21‐39 giga / respectively (30%), pancytopenia found in n = 05 cases (50%), LDH level (mean) = 905 ± 896 IU / L [12‐2,900], n = 02 patients had 1 metabolic complication at diagnosis (hyperkalemia, hyponatremia). n = 8 patients received induction CT (3 + 7), n = 01 patient received only 2 aracytin‐associated antracycline injections. Newborn LAM, the newborn clinically presents: cutaneous and mucosal paleness and hepatosplenomegaly, on the biological plane: GB: 125giga / l, (EB = 64%, blast = 3%), HB = 10 g / dl, PLQ = 13gigal / l, PMO: infiltration by 68% of dystrophic EB, 08% of MB, the newborn t under aseptic vacuum The specific treatment has not yet been started. The complete remission is obtained (n = 04 cases (40%)) and n = 03 failures (30%), n = 01patient came out against medical advice; one induction death is listed (acute cardiac toxicity) • Overall survival = 27% (fig1)Summary/Conclusion:our data are similar to those of the literature: rare pathologic LAM6 (3‐5 / series, 05% in ours), exceptional in children. The signs of bone marrow failure are almost constant, 1 pancytopenia in 50%. Splenomegaly is found in 1/3 of the cases. The prognosis is reserved (overall survival = 25% at 05 years) from wherethe value of rapid diagnosis and adequate managementimage

PS1230 DEFINING THE ROLE OF E‐CADHERIN DURING HEALTHY AND MALIGNANT HEMATOPOIESIS

Background:E‐cadherin is well‐established to prevent tumor formation by acting as a master regulator of cell adhesion and growth factor‐mediated survival signaling in epithelial cells. Aside epithelia, E‐cadherin prominently marks malignant erythroid‐marked precursors in bone marrow (BM) of patients with pure erythroid leukemia (PEL) or Myelodysplastic Syndrome (MDS). Yet the function of E‐cadherin on malignant erythroid precursors is largely unknown and questions the role of E‐cadherin in BM during healthy hematopoiesis.Aims:The overall aim of this study is to identify and characterize E‐cadherin expressing hematopoietic cells and to unmask the role of E‐cadherin during hematopoiesis to obtain novel insights into hematopoietic malignancies.Methods:To assess the role of E‐cadherin during hematopoiesis in BM we generated a hematopoietic‐specific E‐cadherin‐knockout mouse model which revealed a significant reduction of splenic erythroid precursors as examined by multi‐color flow cytometry. Moreover we established E‐cadherin to mark a small uncharacterized hematopoietic cell population of short‐lived erythroid/myeloid hematopoietic progenitor cells (HPCs) in healthy BM of adult mouse by performing colony formation and transplantation experiments.Results:Whereas hematopoiesis is commonly viewed and analyzed by well‐defined ‘markers’. HPC's are generally viewed as cKIT‐positive and Lineage (LIN)‐negative. Our data revealed E‐cadherin to mark undefined Ckit‐dim;LIN‐negative short‐lived HPCs, which we combined with our transplantation data identified as ‘late HPCs’. This poorly defined pool of late HPCs is largely understudied mostly because of the lack of specific markers. As we discovered E‐cadherin to mark late HPCs it will also uniquely allow us to interrogate this population to start to understand where late HPCs localize in the BM, how these cells interact with local and stromal cues and how these cells respond during altered hemostatic conditions.Summary/Conclusion:In this study we show that E‐cadherin is expressed in a small subset of hematopoietic bone marrow cells which display myeloid and erythroid progenitor activity. In addition, somatic inactivation of E‐cadherin in mice causes 50% loss of erythropoietic progenitors in the spleen, but not in the BM.Importantly, as E‐cadherin is markedly expressed in MDS, which onset is displayed by inflammation and the formation of anemia, E‐cadherin may herein act as an important regulator directing myelopoieisis over erythropoiesis upon expression on HPCs during inflammation. In fact, epithelial‐expressed E‐cadherin has been well‐established to directly interact with lymphoid effector NK and T‐cells. Hematopoietic‐expressed E‐cadherin on HPCs may therefore also interact with lymphoid effector cells during inflammation to control myelopoiesis over erythropoiesis during inflammation. We therefore currently explore the consequence of hematopoietic‐specific loss of E‐cadherin during Lymphocytic Choriomeningitis Virus (LCMV)‐driven inflammation and anemia formation to assess whether E‐cadherin may in fact act as a critical regulator of HPC differentiation during inflammation, such as displayed during MDS formation.

PS974 MODELING NKG2D-BASED CAR-T CELL THERAPY IN ANIMALS WITH ACUTE MYELOID LEUKEMIA

Background: Pharmacologic inhibition of pro-survival Bcl-2 family members (Bcl-2, Mcl-1, and BCL-xL) has been extensively studied for acute myeloid leukemia (AML) therapy. This has led to the recent approval of the Bcl-2 inhibitor venetoclax. Primary resistance to venetoclax is commonly associated with overexpression of Mcl-1 and Bcl-xL, suggesting heterogeneity in dependence on Bcl-2 family members between AML patients. In healthy bone marrow (BM), Bcl-xL is essential for effective development of the erythroid lineage. Pure erythroid leukemia (PEL) and erythroleukemia (MDS), formerly classified as acute erythroid leukemia (AEL, FAB M6), are malignancies arising from the erythroid lineage. Thus, we hypothesized that targeting BCL-xL could represent a viable therapy option for leukemias with erythroid features. Aims: We aimed to assess the expression levels of Bcl-2 family members across different leukemia subtypes and to study whether Bcl-xL would be a viable drug target for AEL using large-scale functional genomic and ex vivo drug screening data. Methods: Publicly available transcriptomic datasets, including DMAP, TCGA, HEMAP, and CCLE, were used to compare gene expression in healthy samples, primary leukemia samples and AML cell lines. Genome-wide RNAi and CRISPR-Cas9 loss-of-function screening data from the DepMap project was used to evaluate essential genes for AEL cell lines. Drug screening was performed with 528 compounds across a 10,000-fold concentration range using 21 AML cell lines involving five AEL cases (F-36P, OCI-M1, TF-1, HEL, and KG-1). Protein levels of Mcl-1, Bcl-2, and Bcl-xL were assessed from the same cell lines with Western blot analysis. Drug testing was also performed for three primary AEL patient samples. Results: BCL2L1 (Bcl-XL) was strikingly overexpressed in the healthy erythroid lineage (DMAP) and also in the AEL (FAB M6) when compared to other leukemias and AML FAB subtypes in both TCGA and Hemap datasets (Figure). Reflecting the expression pattern in primary patient samples, AML cell lines derived from AEL expressed elevated levels of BCL2L1 and decreased levels of MCL1 and BCL2. Interestingly, also AML cell lines derived from megakaryoblastic leukemia (CMK and M-07e) showed similar trend. The analysis of genome-wide RNAi and CRISPR-Cas9 screening data identified BCL2L1 as the most selective vulnerability in the erythroid and megakaryocytic cell lines (HEL, TF-1, CMK, MOLM16, and F-36P) when compared to other 18 cell lines belonging to different AML FAB subtypes. Accordingly, amongst the 528 anticancer compounds Bcl-xL inhibitors, A-1331852 and A-1155463, were the most selectively effective compounds in erythroid and megakaryocytic cell lines. In contrast, venetoclax targeting Bcl-2 and S-63845 targeting Mcl-1 were effective in other AML subtypes but not in AEL cell lines. The observed druggable antiapoptotic protein dependencies were also reflected in the protein levels. Finally, primary AEL samples showed pronounced sensitivity to A-1331852 and A-1155463 when compared to other AML samples.Summary/Conclusion: Given the high expression of Bcl-xL in erythroid leukemia and the lack of molecularly targeted therapy options, Bcl-xL is a promising target for further exploration in treatment of leukemias with erythroid features.

PS973 BCL‐XL AS A PUTATIVE THERAPY TARGET IN ACUTE ERYTHROID LEUKEMIA

Background:Pharmacologic inhibition of pro‐survival Bcl‐2 family members (Bcl‐2, Mcl‐1, and BCL‐xL) has been extensively studied for acute myeloid leukemia (AML) therapy. This has led to the recent approval of the Bcl‐2 inhibitor venetoclax. Primary resistance to venetoclax is commonly associated with overexpression of Mcl‐1 and Bcl‐xL, suggesting heterogeneity in dependence on Bcl‐2 family members between AML patients. In healthy bone marrow (BM), Bcl‐xL is essential for effective development of the erythroid lineage. Pure erythroid leukemia (PEL) and erythroleukemia (MDS), formerly classified as acute erythroid leukemia (AEL, FAB M6), are malignancies arising from the erythroid lineage. Thus, we hypothesized that targeting BCL‐xL could represent a viable therapy option for leukemias with erythroid features.Aims:We aimed to assess the expression levels of Bcl‐2 family members across different leukemia subtypes and to study whether Bcl‐xL would be a viable drug target for AEL using large‐scale functional genomic and ex vivo drug screening data.Methods:Publicly available transcriptomic datasets, including DMAP, TCGA, HEMAP, and CCLE, were used to compare gene expression in healthy samples, primary leukemia samples and AML cell lines. Genome‐wide RNAi and CRISPR‐Cas9 loss‐of‐function screening data from the DepMap project was used to evaluate essential genes for AEL cell lines. Drug screening was performed with 528 compounds across a 10,000‐fold concentration range using 21 AML cell lines involving five AEL cases (F‐36P, OCI‐M1, TF‐1, HEL, and KG‐1). Protein levels of Mcl‐1, Bcl‐2, and Bcl‐xL were assessed from the same cell lines with Western blot analysis. Drug testing was also performed for three primary AEL patient samples.Results:BCL2L1 (Bcl‐XL) was strikingly overexpressed in the healthy erythroid lineage (DMAP) and also in the AEL (FAB M6) when compared to other leukemias and AML FAB subtypes in both TCGA and Hemap datasets (Figure). Reflecting the expression pattern in primary patient samples, AML cell lines derived from AEL expressed elevated levels of BCL2L1 and decreased levels of MCL1 and BCL2. Interestingly, also AML cell lines derived from megakaryoblastic leukemia (CMK and M‐07e) showed similar trend. The analysis of genome‐wide RNAi and CRISPR‐Cas9 screening data identified BCL2L1 as the most selective vulnerability in the erythroid and megakaryocytic cell lines (HEL, TF‐1, CMK, MOLM16, and F‐36P) when compared to other 18 cell lines belonging to different AML FAB subtypes. Accordingly, amongst the 528 anticancer compounds Bcl‐xL inhibitors, A‐1331852 and A‐1155463, were the most selectively effective compounds in erythroid and megakaryocytic cell lines. In contrast, venetoclax targeting Bcl‐2 and S‐63845 targeting Mcl‐1 were effective in other AML subtypes but not in AEL cell lines. The observed druggable antiapoptotic protein dependencies were also reflected in the protein levels. Finally, primary AEL samples showed pronounced sensitivity to A‐1331852 and A‐1155463 when compared to other AML samples.Summary/Conclusion:Given the high expression of Bcl‐xL in erythroid leukemia and the lack of molecularly targeted therapy options, Bcl‐xL is a promising target for further exploration in treatment of leukemias with erythroid features.image