Leukemia Research Reports最新文献

{"title":"HAPLOINSUFFICIENCY OF TIE2 IN MUTATED BLOOD CELLS SUPPRESS ANGIOGENESIS IN THE BONE MARROW AND INHIBIT PROGRESSION OF MDS","authors":"M. Hirayama,&nbsp;Y. Arima,&nbsp;T. Suda,&nbsp;G. Sashida","doi":"10.1016/j.lrr.2024.100430","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100430","url":null,"abstract":"<div><h3>Introduction</h3><p>Tie2 is a receptor tyrosine kinase and regulates angiogenesis and vascular quiescence. Given that Tie2 modulates microvascular density in cancer, we hypothesized that deletion of Tie2 in blood cells can inhibit progression of myelodysplastic syndrome (MDS). We attempted to understand the role of Tie2 in development of MDS by using an Ezh2/Tet2 double knock out (DKO) mouse model.</p></div><div><h3>Methods</h3><p>We transplanted bone marrow (BM) cells isolated from Cre-ERT2 mice, Tie2^flox/wt; Cre-ERT2 mice, Ezh2^flox/flox; Tet2^flox/flox; Cre-ERT2 mice, Ezh2^flox/flox; Tet2^flox/flox; Tie2^flox/wt; Cre-ERT2 mice and Ezh2^flox/flox; Tet2^flox/flox; Tie2^flox/flox; Cre-ERT2 mice into lethally-irradiated Ly5.1⁺ recipient mice. Ezh2, Tet2 and Tie2 genes were deleted by administration of tamoxifen one month post the transplantation.</p></div><div><h3>Results</h3><p>We found that Ezh2^−/−Tet2^−/- DKO, Ezh2^−/−Tet2^−/- Tie2^+/− (DKOTie2^+/−) and Ezh2^−/−Tet2^−/- Tie2^−/− TKO mice all developed MDS and MDS/MPN, showing anemia and dysplastic cells in the peripheral blood (PB) and the BM; however, DKOTie2^+/− mice showed significantly longer survival than did DKO mice and TKO mice. While DKO mice showed deformed CD31⁺ endothelial cells and increased vascular density in the BM, DKOTie2^+/− mice mitigated the altered vascular formation in the BM. RNA-sequencing revealed that DKOTie2^+/− stem cells repressed expression of genes involved in interferon, cell cycles and angiogenesis, compared to DKO stem cells, suggesting that the haploinsufficiency of Tie2 impaired the property of MDS cells to drive angiogenesis in the BM, resulting in the delayed development of MDS.</p></div><div><h3>Conclusions</h3><p>We are now working on the molecular mechanism of how the Tie2 gene in blood cells modulates the angiogenesis to drive the progression of MDS.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100430"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000207/pdfft?md5=cd3401a401a00c19c7efc7dda86ac215&pid=1-s2.0-S2213048924000207-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIGNATURES OF SOMATIC GENETIC RESCUE IN SAMD9/9L SYNDROMES: DIAGNOSTIC AND PROGNOSTIC UTILITY","authors":"N. Gray,&nbsp;M. Boals,&nbsp;S. Lewis,&nbsp;M. Yoshida,&nbsp;S. Sahoo,&nbsp;M. Wlodarski","doi":"10.1016/j.lrr.2024.100432","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100432","url":null,"abstract":"<div><h3>Introduction</h3><p>Germline SAMD9 and SAMD9L mutations (SAMD9/9L^mut) cause a novel bone marrow failure and pediatric myelodysplastic syndrome. Despite &gt;400 patients reported, evaluating variants remains challenging with &gt;70% of germline SAMD9/9L^mut classified as variants of uncertain significance, mainly due to heterogenous phenotypes and lack of functional assays. Many patients acquire compensatory clones including secondary SAMD9/9L^mut and UPD7q with loss of the mutant allele, along with maladaptive, stress-induced monosomy 7. Monosomy 7 poses unique surveillance challenges as it may disappear spontaneously over time, precluding the need for HSCT.</p></div><div><h3>Methods</h3><p>We utilized our prospective somatic surveillance database to identify genetic patterns and evolution in SAMD9/9L^mut patients (median age 8 years). Using high-sensitivity myeloid gene panel and SNP array, we evaluated hematopoietic specimens of 23 patients with SAMD9/9L syndromes. For comparison, we analyzed a cohort of 132 patients with other BMF/MDS conditions. Serial analysis was performed in 39% (61/155) of patients for a median duration of 15.7 (1.4-53.2) months.</p></div><div><h3>Results</h3><p>We found 33 somatic SAMD9/9L^mut in 61% (14/23), UPD7q in 26% (6/23), and monosomy 7 in 48% (11/23) of patients with germline SAMD9/9L^mut. Somatic SAMD9/9L^mut and UPD7q were not identified in the comparative cohort, resulting in 100% specificity and positive predictive value to rule-in germline SAMD9/9L syndromes. Notably, no patient (including monosomy 7 cases) developed advanced MDS, leukemia, or cancer driver mutations with up to 4.4 years of follow-up.</p></div><div><h3>Conclusions</h3><p>Somatic SAMD9/9L^mut and UPD7q act as a “natural functional assay” confirming pathogenicity of germline SAMD9/9L^mut. Despite high rates of monosomy 7, leukemic progression is rare in SAMD9/9L syndromes.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100432"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000220/pdfft?md5=ea9fddb27301304a0dcf910a836b7ce7&pid=1-s2.0-S2213048924000220-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NK-CELLS TRAFFIC TO THE BONE MARROW AS A POTENTIAL IMMUNOLOGICAL MECHANISM OF ACTION OF HYPOMETHYLATING AGENTS FOR HIGH-RISK MDS AND AML","authors":"J. Hong ,&nbsp;R. Ramaswamy ,&nbsp;S. Min ,&nbsp;J. Park ,&nbsp;C. Fielder ,&nbsp;Q. Hu ,&nbsp;S.-S. Yoon ,&nbsp;T.K. Kim","doi":"10.1016/j.lrr.2024.100441","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100441","url":null,"abstract":"<div><h3>Introduction</h3><p>In addition to direct cytotoxic effect of hypomethylaging agents (HMAs) on myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) cells, HMA upregulates effector T-cell function by demethylating T-cell exhaustion-associated genes (Hazem, Cell 2017) or trafficking effector T-cells to bone marrow (BM) by Th1-type chemokines activation (Peng, Nature 2019). We tried to elucidate dynamic changes of immune cells profile and gene expression after HMA treatment in patients with MDS or AML.</p></div><div><h3>Methods</h3><p>We performed scRNAseq on consecutive BM samples from an high-risk MDS (HR-MDS) patient treated with azacitidine: we categorized cell clusters based on immune-cell types, assessed changes in immune-cell proportions following treatment, and conducted a differentially expressed genes (DEG) analysis. In addition, changes in immune-cells proportions before vs. after HMA treatment in HR-MDS patients were evaluated, and the association between the immune-cell proportions changes and response to HMA were analyzed from seuqential BM aspirates from HR-MDS/AML patients.</p></div><div><h3>Results</h3><p>In the scRNAseq data, the NK-cell cluster exhibited the most significant increase in the relative proportion up to response, whereas the effector T-cells clusters showed only a modest increase of proportion upon HMA response. DEG revealed an overexpression of CXCR4 in the NK-cell cluster at the timepoint of response, suggesting the recruitment of NK cells to BM. The trafficking of NK cells to BM after HMA response were reproduced in serial BM aspirates from patients with HR-MDS/AML.</p></div><div><h3>Conclusions</h3><p>NK-cells recruited into BM through CXCR4 overexpression and anti-leukemic cytotoxicity exerted by NK cells may represent a crucial immunological mechanism of action for HMAs in patients with HR-MDS/AML.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100441"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000311/pdfft?md5=b5cb133a14525c3fd22aa632144a000d&pid=1-s2.0-S2213048924000311-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TPO AGONIST RESCUED DEVELOPMENTAL HEMATOPOIETIC STEM CELL IN HEREDITARY BONE MARROW FAILURE SYNDROME","authors":"M. Mochizuki,&nbsp;A. Nakamura-Ishizu","doi":"10.1016/j.lrr.2024.100438","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100438","url":null,"abstract":"<div><h3>Introduction</h3><p>Fanconi Anemia (FA) gene is a congenital bone marrow failure (BMF) disorder caused by impaired replication stress (RS) associated DNA damage repair. We previously described FA fetal liver (FL) hematopoietic stem cell (HSC) exhibited high mitochondrial oxidative phosphorylation (OXPHOS) and mitophagy when it was under RS. Thrombopoietin (TPO) signaling is known to modulate mitochondria metabolism in HSC. While TPO agonists are utilized for the treatment of BMFs such as aplastic anemia, whether and how these drugs can affect FA and its progression to hematopoietic malignancy is unknown.</p></div><div><h3>Methods</h3><p>To clarify the TPO signal of response in FA, we analyzed FA mice [an1] treated with TPO agonists or crossed with TPO-deficient mice.</p></div><div><h3>Results</h3><p>Embryonic mice FA fetal liver HSCs were rescued with TPO agonist administration. TPO deficiency no rescued FA FL HSC phenotype.</p></div><div><h3>Conclusions</h3><p>TPO signal confers developmental FA HSC deficit. Further investigation is needed to describe the mechanism and efficiency.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100438"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000281/pdfft?md5=b07d70f4547652223cccdff9939dbb8d&pid=1-s2.0-S2213048924000281-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EFFICACY AND SAFETY OF LUSPATERCEPT VERSUS EPOETIN ALFA IN ERYTHROPOIESIS-STIMULATING AGENT (ESA)-NAIVE PATIENTS WITH TRANSFUSION-DEPENDENT LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS): FULL ANALYSIS OF THE COMMANDS TRIAL","authors":"G. Garcia-Manero ,&nbsp;U. Platzbecker ,&nbsp;V. Santini ,&nbsp;A. Zeidan ,&nbsp;P. Fenaux ,&nbsp;R. Komrokji ,&nbsp;J. Shortt ,&nbsp;D. Valcarcel ,&nbsp;A. Jonasova ,&nbsp;S. Dimicoli-Salazar ,&nbsp;I.S. Tiong ,&nbsp;C.-C. Lin ,&nbsp;J. Li ,&nbsp;J. Zhang ,&nbsp;A.C. Giuseppi ,&nbsp;S. Kreitz ,&nbsp;V. Pozharskaya ,&nbsp;K. Keeperman ,&nbsp;S. Rose ,&nbsp;T. Prebet ,&nbsp;M. Della Porta","doi":"10.1016/j.lrr.2024.100447","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100447","url":null,"abstract":"<div><h3>Introduction</h3><p>We report the full analysis of the COMMANDS trial assessing efficacy and safety of luspatercept versus epoetin alfa (EA) in ESA-naive patients with LR-MDS.</p></div><div><h3>Methods</h3><p>363 patients (aged ≥18 y, with transfusion-dependent LR-MDS, serum erythropoietin &lt;500 U/L) were randomized 1:1 to luspatercept or EA. Primary endpoint was achievement of red blood cell transfusion independence (RBC-TI) ≥12 wk with concurrent mean hemoglobin increase ≥1.5 g/dL (wk 1–24). Secondary endpoints included achievement of RBC-TI ≥12 and 24 wk, hematologic improvement–erythroid (HI-E) ≥8 wk (wk 1–24), RBC-TI ≥12 wk duration, and safety.</p></div><div><h3>Results</h3><p>As of 31Mar2023, 110/182 (60.4%) luspatercept-treated versus 63/181 (34.8%) EA-treated patients achieved the primary endpoint (<em>P</em>&lt;0.0001). Primary endpoint achievement favored luspatercept in most subgroups including region. Median (range) treatment duration was 51.3 (3–196) and 37.0 (1–202) wk for luspatercept versus EA. 68.1% and 48.6% of luspatercept- versus EA-treated patients, respectively, achieved RBC-TI ≥12 wk; 47.8% and 30.9% achieved RBC-TI 24 wk; 74.4% and 53.0% achieved HI-E ≥8 wk. Median (95% CI) duration of RBC-TI ≥12 wk was 128.1 wk (108.3–not estimable [NE]) with luspatercept versus 89.7 wk (55.9–157.3) with EA (HR, 0.534; Figure). 2.7% and 3.3% of luspatercept- and EA-treated patients, respectively, progressed to AML; 97.8% and 92.2% reported any-grade treatment-emergent adverse events (TEAEs); 58.5% and 49.2% reported grade 3/4 TEAEs. Death rates on- and post-treatment were similar between arms.</p></div><div><h3>Conclusions</h3><p>RBC-TI duration and erythroid responses achieved with luspatercept were superior to EA. Luspatercept safety results were consistent with previous MDS studies.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100447"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000372/pdfft?md5=ddb857b2362c3a3340ae78d38512a9a4&pid=1-s2.0-S2213048924000372-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venetoclax for an ATRA and ATO resistance acute promyelocytic leukemia patient with TNRC18::RARA fusion gene","authors":"Weina Li ,&nbsp;Haijie Li ,&nbsp;Xueyan Chen ,&nbsp;Yan Zheng","doi":"10.1016/j.lrr.2024.100482","DOIUrl":"10.1016/j.lrr.2024.100482","url":null,"abstract":"<div><div>Variant acute promyelocytic leukemia (APL) poses diagnostic and therapeutic challenges primarily because of the absence of <em>PML::RARA.</em> This report presents the case of a patient diagnosed with <em>all-trans</em> retinoic acid (ATRA)-resistant APL harboring the <em>TNRC18::RARA</em> fusion gene. After treatment with venetoclax, azacitidine, and ATRA, the patient achieved complete remission. The patient also developed pulmonary tuberculosis and a multidrug-resistant infection, which improved considerably after antituberculosis treatment and carrimycin, respectively.</div></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"22 ","pages":"Article 100482"},"PeriodicalIF":0.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Avapritinib treatment of aggressive systemic mastocytosis with a novel KIT exon 17 mutation","authors":"Lyndsey Sandow ,&nbsp;Ajia Town ,&nbsp;Michael C. Heinrich","doi":"10.1016/j.lrr.2023.100409","DOIUrl":"https://doi.org/10.1016/j.lrr.2023.100409","url":null,"abstract":"<div><h3>Background</h3><p>Systemic mastocytosis is a rare hematologic malignancy that leads to the accumulation of neoplastic mast cells in the bone marrow, visceral organs, and skin. Mutations in the receptor tyrosine kinase, KIT are seen in most patients with systemic mastocytosis. The most common mutation is a gain of function mutation in KIT D816V. Avapritinib is a highly selective KIT D816V inhibitor approved for the treatment of advanced systemic mastocytosis. Recent studies have also suggested that avapritinib is active across other KIT mutations located in exon 11 and exon 17.</p></div><div><h3>Case Presentation</h3><p>A 68 year old woman was referred for a history of lymphadenopathy and diarrhea and was ultimately found to have systemic mastocytosis with involvement in her bone marrow, gastrointestinal tract, liver, and spleen. The bone marrow biopsy reveled a novel KIT p.D816-N822delinsMIDSI mutation in exon 17. The patient was started on avapritinib leading to significant decrease in the frequency of her diarrhea and a significant reduction in her tryptase levels. Her course was complicated by arthralgias leading to a decrease in her avapritinib dose and ultimately a degranulation episode requiring hospitalization. Following dose re-escalation, patient has remained clinically stable without any further adverse events.</p></div><div><h3>Conclusion</h3><p>We report a case of aggressive systemic mastocytosis with a novel KIT mutation on exon 17 treated with avapritinib leading to a sustained response. While avapritinib is known as a potent inhibitor against the D816V mutation, our case suggests that it may also be effective against other rare KIT mutations in systemic mastocytosis offering more potential treatment options in patients with rare mutations.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100409"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048923000493/pdfft?md5=0eee6858a41cb33a1be31e66b68a4b0d&pid=1-s2.0-S2213048923000493-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139108503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma cell leukemia with soft tissue involvement; reporting a rare case","authors":"Ahmed Bendari ,&nbsp;Rahaf M. Abu Khalaf ,&nbsp;Sunder Sham ,&nbsp;Reham Al-Refai ,&nbsp;Oana Vele ,&nbsp;Alyssa Yurovitsky","doi":"10.1016/j.lrr.2024.100411","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100411","url":null,"abstract":"<div><p>Plasma cell leukemia (PCL) is a rare aggressive variant of multiple myeloma. PCL is diagnosed when clonal plasma cells constitute more than 20 % of the total circulating leukocytes or when the absolute plasma cell count exceeds 2 × 10⁹ /L. Extramedullary involvement including cavity effusion is frequently seen at the time of diagnosis. However, soft tissue involvement is rarely encountered with only one published case in the English literature. We report a 74-year-old man, who presented with progressive shortness of breath over a few months. Laboratory studies showed leukocytosis (32 × 109 /L) with 26 % peripheral plasmacytoid cells and significantly elevated lactate dehydrogenase (&gt; 2500 U/L). Serum protein electrophoresis detected a monoclonal IgG lambda band. A 7.4 cm left hilar mass, bilateral pleural effusion, and multiple fluorodeoxyglucose (FDG)-avid subcutaneous nodules in the pelvic and gluteal regions were demonstrated on imaging. Gluteal nodule biopsy revealed diffuse infiltrative CD138+ and MUM1+ cells with aberrant CD4, CD30, and BCL2 expression. The Ki-67 proliferation index was 70 %. Bone marrow biopsy showed sheets of atypical plasma cells with lambda-restriction and CD138 and MUM1 expression without cyclin D1 and CD20 expression. These cells comprise approximately 70–80 % of the bone marrow cellularity. A similar immunophenotype was demonstrated in peripheral and bone marrow flow cytometry. Molecular and cytogenetics showed an abnormal clone with a complex karyotype including monosomy 13 and 14q deletion. Overall, these findings are consistent with a plasma cell neoplasm. Our case study illustrates soft tissue involvement in PCL, which is rarely seen.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100411"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000013/pdfft?md5=be4ca13748083953664037e163c94181&pid=1-s2.0-S2213048924000013-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139433843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute myeloid leukemia with a novel AKAP9::PDGFRA fusion transformed from essential thrombocythemia: A case report and mini review","authors":"Yavuz Sahin ,&nbsp;Jianming Pei ,&nbsp;Don A. Baldwin ,&nbsp;Nashwa Mansoor ,&nbsp;Lori Koslosky ,&nbsp;Peter Abdelmessieh ,&nbsp;Y. Lynn Wang ,&nbsp;Reza Nejati ,&nbsp;Joseph. R. Testa","doi":"10.1016/j.lrr.2024.100465","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100465","url":null,"abstract":"<div><p>Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark <em>CALR</em> mutation transforming to AML characterized by a previously unreported <em>AKAP9::PDGFRA</em> fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100465"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000554/pdfft?md5=61cd70a7f26e97e6afe74f7343ef5f35&pid=1-s2.0-S2213048924000554-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141250067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"THE ROLE OF LET-7/HMGA2 LINKAGE IN THE PATHOGENESIS AND PROGNOSIS OF MYELODYSPLASTIC NEOPLASMS","authors":"D. Vlachopoulou ,&nbsp;C.-N. Kontandreopoulou ,&nbsp;P.T. Diamantopoulos ,&nbsp;S. Syriopoulou ,&nbsp;C. Stafylidis ,&nbsp;P. Katsiampoura ,&nbsp;A. Galanopoulos ,&nbsp;M. Dimou ,&nbsp;P. Panayiotidis ,&nbsp;N.-A. Viniou","doi":"10.1016/j.lrr.2024.100428","DOIUrl":"https://doi.org/10.1016/j.lrr.2024.100428","url":null,"abstract":"<div><h3>Introduction</h3><p>MicroRNAs (miRNAs),are significant regulators of human hematopoietic stem cells. Their deregulation contributes to hematological malignancies.The let-7 family has been found frequently deregulated in malignancies.In MDS various alterations of miRNAs have been reported.High Mobility Group AT-Hook 2 (HMGA2) protein functions as a transcriptional regulator. In this study, we investigated the HMGA2 expression in MDS and specifically in patients with fibrosis we studied the prognostic significance of four members of the let-7 family (let-7a, let-7b, let-7c, let-7d).</p></div><div><h3>Methods</h3><p>RNA extraction, reverse transcription, anda SYBR Green based real-time PCR were performed for the absolute quantification of HMGA2, using standard protocols. After RNA polyadenylation and reverse transcription with an oligo-dT adapter primer, miRNAs transcript levels were determined using the SYBR Green chemistry. IBM SPSS statistics, version 26 (IBM Corporation, North Castle, NY, USA) was used for the analysis.</p></div><div><h3>Results</h3><p>HMGA2 gene expression was investigated in 78 patients with MDS, whereas transcript levels of four members of the let-7 family (let-7a, let-7b, let-7c, let-7d) were analyzed in 11 patients with fibrosis. Let-7a transcript levels were significantly higher in MDS patients who developed acute myeloid leukemia (AML) compared to the group that did not (p=0.0141). Let-7d presented a negative correlation (p=0.0408). A moderate (p =0.0483) negative correlation of HMGA2 with let-7c, and a strong positive correlation (p =0.0481) with let-7d, were observed.</p></div><div><h3>Conclusions</h3><p>In literature, the let-7/HMGA2 linkage could be a signature in MDS pathogenesis. Let-7a level was found higher in transformation to AML,defining it as a poor prognostic factor, in contrast with the protective role of high let-7d.</p></div>","PeriodicalId":38435,"journal":{"name":"Leukemia Research Reports","volume":"21 ","pages":"Article 100428"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2213048924000189/pdfft?md5=5918d5e24efc7086c03e1df509bcef87&pid=1-s2.0-S2213048924000189-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140103588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}