scholarly journals Clonal Evolution of B-Cell Acute Lymphoblastic Leukemia with del(9)(p13p21) into Mixed Phenotype Acute Leukemia Presenting as an Isolated Testicular Relapse

Reports ◽  
2019 ◽  
Vol 2 (3) ◽  
pp. 18 ◽  
Author(s):  
Miller ◽  
Park ◽  
Saxe ◽  
Lew ◽  
Raikar
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Acute Leukemias ◽  
Cytogenetic Aberrations ◽  
Mixed Phenotype Acute Leukemia ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Mixed Phenotype

Lineage switch in acute leukemias is a well-reported occurrence; however, most of these cases involve a switch from either lymphoid to myeloid or myeloid to lymphoid lineage. Here, we report a case of a 14-year-old male with B-cell acute lymphoblastic leukemia (B-ALL) who initially responded well to standard chemotherapy but then later developed mixed phenotype acute leukemia (MPAL) at relapse, likely reflecting a clonal evolution of the original leukemia with a partial phenotypic shift. The patient had a del(9)(p13p21) in his leukemia blasts at diagnosis, and the deletion persisted at relapse along with multiple additional cytogenetic aberrations. Interestingly, the patient presented with an isolated testicular lesion at relapse, which on further analysis revealed both a lymphoid and myeloid component. Unfortunately, the patient did not respond well to treatment at relapse and eventually succumbed to his disease. To our knowledge, an isolated extramedullary MPAL at relapse in a patient with previously diagnosed B-ALL has not been reported in the literature before.

scholarly journals Poor Prognosis Biomolecular Factors Are Highly Frequent in Childhood Acute Leukemias From Oaxaca, Mexico

2020 ◽  
Vol 19 ◽  
pp. 153303382092843
Author(s):  
Gerardo Juárez-Avendaño ◽  
Nuria Citlalli Luna-Silva ◽  
Euler Chargoy-Vivaldo ◽  
Laura Alicia Juárez-Martínez ◽  
Mayra Noemí Martínez-Rangel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Acute Leukemias ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Acute Myeloid

Objective: To investigate the cellular and molecular epidemiology of acute leukemias in vulnerable populations of children and adolescents in Oaxaca de Juarez, Mexico. Material and Methods: Descriptive, cross-sectional and retrospective study, conducted from 2014 to 2018 in which profiles of molecular and immunophenotypic aberrations were investigated in children and adolescents diagnosed with acute leukemia, by evaluating 28 molecular abnormalities by HemaVision-Q28 multiplex RT-PCR kit and standardized EuroFlow Immunophenotyping of bone marrow cells. Results: We included 218 patients, with 82.5% younger than 14 years and 17.5% adolescents. The median age was 9 years and a main peak of incidence was recorded at age of 4 to 5 years. B-cell acute lymphoblastic leukemia was diagnosed in 70.64% of all cases, acute myeloid leukemia was in 22.48%, T-cell acute lymphoblastic leukemia in 6.42%, and mixed lineage acute leukemia in 0.46% of cases. Overall, chromosomal translocations were positive in 29.82% of cases. While 65.31% of patients with acute myeloid leukemia reported aberrancies, only in 18.83% of B-cell acute lymphoblastic leukemia cases genetic abnormalities were obvious. Surprisingly, most prevalent translocations in B-cell acute lymphoblastic leukemia were t(9;22) in 20.7%, followed by t(4;11) in 17.2% and t(6;11) in 13.8%, whereas patients with acute myeloid leukemia showed t(15;17) in 40.6% and t(8;21) in 21.9%. In contrast, an homogeneous expression of t(3;21) and t(6;11) was recorded for T-cell acute lymphoblastic leukemia and mixed lineage acute leukemia cases, respectively. Except for t(1;19), expressed only by pre-B cells, there was no association of any of the studied translocations with differentiation stages of the B-leukemic developmental pathway. Conclusion: Our findings identify near 50% of patients with acute lymphoblastic leukemia at debut with high-risk translocations and poor prognosis in B-cell acute lymphoblastic leukemia as well as an unexpected increase of acute myeloid leukemia cases in young children, suggesting a molecular shift that support a higher incidence of poor prognosis cases in Oaxaca.

Successful acute lymphoblastic leukemia-type therapy in two children with mixed-phenotype acute leukemia

2016 ◽  
Vol 58 (10) ◽  
pp. 1072-1076 ◽  
Author(s):  
Keisuke Otsubo ◽  
Miharu Yabe ◽  
Hiromasa Yabe ◽  
Akiko Fukumura ◽  
Tsuyoshi Morimoto ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Mixed Phenotype Acute Leukemia ◽  
Mixed Phenotype

scholarly journals Deletion of genes encoding PU.1 and Spi-B leads to B cell acute lymphoblastic leukemia associated with driver mutations in Janus Kinases

2018 ◽  
Author(s):  
Carolina R. Batista ◽  
Michelle Lim ◽  
Anne-Sophie Laramée ◽  
Faisal Abu-Sardanah ◽  
Li S. Xu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Amino Acid ◽  
Mouse Model ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Janus Kinases ◽  
Cell Acute Lymphoblastic Leukemia

AbstractPrecursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with recurrent mutations that occur in cancer-initiating cells. There is a need to understand how spontaneous driver mutations influence clonal evolution in leukemia. The ETS-transcription factors PU.1 and Spi-B (encoded bySpi1andSpib) execute a critical role in B cell development and serve as complementary tumour suppressors by opposing the proliferative events mediated by IL-7R signaling. Here, we used a mouse model to conditionally deleteSpi1andSpibgenes in developing B cells. These mice developed B-ALL with a median time to euthanasia of 18 weeks. We performed RNA and whole-exome sequencing (WES) on leukemias isolated from Mb1-CreΔPB mice and identified single-nucleotide variants (SNVs) inJak1,Jak3andIkzf3genes, resulting in amino acid changes and in the gain of early stop-codons. JAK3 mutations resulted in amino acid substitutions located in the pseudo-kinase (R653H, V670A) and in the kinase (T844M) domains. Introduction of these mutations into wild-type pro-B cells conferred survival and proliferation advantages. We conclude that mutations in Janus kinases represent secondary drivers of leukemogenesis in the absence of Spi-B and PU.1 transcription factors. This mouse model represents an useful tool to study clonal evolution and tumour heterogeneity in B-ALL.

scholarly journals Myelodysplastic Syndrome with Myelofibrosis Transformed to a Precursor B-Cell Acute Lymphoblastic Leukemia: A Case Report with Review of the Literature

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ayed A. Algarni ◽  
Mojtaba Akhtari ◽  
Kai Fu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Review Of The Literature ◽  
Acute Leukemias ◽  
Allogenic Stem Cell Transplantation ◽  
Increased Risk ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Acute Myeloid

Myelodysplastic syndromes (MDS) comprise a group of heterogeneous clonal hematopoietic cell disorders characterized by cytopenias, bone marrow hypercellularity, and increased risk of transformation to acute leukemias. MDS usually transformed to acute myeloid leukemia, and transformation to acute lymphoblastic leukemia (ALL) is rare. Herein, we report a unique patient who presented with MDS with myelofibrosis. Two months after the initial diagnosis, she progressed to a precursor B-cell acute lymphoblastic leukemia. She was treated with induction therapy followed by allogenic stem cell transplantation. She was alive and doing well upon last followup. We have also reviewed the literature and discussed the clinicopathologic features of 36 MDS patients who progressed to ALL reported in the literature.

scholarly journals Clinical Characteristics and Outcomes of 82 Patients with Mixed-Phenotype Acute Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1124-1124
Author(s):  
Yan chun Yang ◽  
Ya Gao ◽  
Ying Xu ◽  
Yintian Zhang ◽  
Dongmao Zhu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Guangdong Province ◽  
Hybrid Therapy ◽  
Mixed Phenotype Acute Leukemia ◽  
Mixed Phenotype ◽  
Acute Myeloid

Abstract Objectives: Mixed-phenotype acute leukemia(MPAL) is a rare disease and comprises 2% to 5% of all acute leukemia. Outcomes for MPAL are worse than both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).The complex phenotype exhibited by this type of leukemia resulted in a myriad of treatment approaches.In our study, we retrospective analysis 82 patients in clinical trail, treatment strategy and prognosis. Method: eighty-two patients diagnosed with MPAL at Nan fang hospital from 2006 to 2017 using either EGIL or 2008 WHO criteria were analyzed. Comparison the treatment effect and outcomes between different therapy types. Result: eighty-two patients, including 60 males and 22 females with a median age of 29 years (range, 2 months-72 years), were studied. 61 patients (77%) were older than 18years, 73patients met the criteria for MPAL via EGIL, 68via WHO2008, and 59of these were reported to satisfy both definitions. fifty one of these cases (62.2%) had a B/myeloid phenotype, Twenty four of these cases (29.3%) had a T/myeloid phenotype. The other cases (8.5%) showed immunophenotypic evidence of a B, T, and myeloid lineage in one blast population. Among the 82 cases, 57 cases with successful cytogenetic studies, 20(35.1%) had normal karyotypes and 37patients(64.9%) had abnormal karyotypes. Twelve patients (21.05%) translocation between chromosomes 9 and 22, five (8.8%) patients had 11q23/MLL translocations. Twelve patients (21.05%) had a complex karyotype and eight patients (14%) had other karyotype. The rarity of this disease and the fact that patients with MPAL are excluded from most AML and ALL clinical trials further complicates guidance about therapy. Of the 82 cases, 75 patients underwent the complete first course of treatment and complete remission rate was 49.8%. treatment approaches utilizing therapy for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and so-called "hybrid" therapy mixing elements of both are 51.9%, 16.7% and 66.7% respectively (P=0.003).OS and EFS with hybrid induction therapy and ALL like induction were not significantly different than those with AML induction by either definition (P>0.05). A total of 60 patients received consolidation treatment, 21 patients received the chemotherapy while 39 patients received stem cell transplant (HSC). The total Median EFS was 21months, in Chemotherapy group and HSC group, the Median EFS was 6 months and 40 months respectively, The 3-year EFS was 26.1% and 55.6% respectively (P=0.038). The total Median OS was 21 months, Median OS showed a significant survival benefit for starting with chemotherapy as compared to HSC( 12 months and 43 months respectively (P=0.001)), The 3-year OS was 19.1% and 57.7% respectively. Conclusion: In this study, ALL like induction therapy or "hybrid" therapy was associated with a more than three-fold greater CR rate than AML therapy. SCT therapy showed a trend for an association with higher OS and EFS for MPAL . Key words: MPAL, Immunophenotype,Treatment strategy Funding Key Sci-Tech Research Projects of Guangdong Province (2014A02021102). Disclosures Fan: National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.

scholarly journals Subclonal Variation of RAG-Mediated Diversification in B Cell Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3955-3955
Author(s):  
Carol Fries ◽  
Diana G Adlowitz ◽  
Philip J Rock ◽  
Janice M Spence ◽  
John P Spence ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Deep Sequencing ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Analysis Tool ◽  
Single Patient ◽  
Cell Acute Lymphoblastic Leukemia

Background: Recombination-activating gene (RAG) mediates recombination of the immunoglobulin heavy chain variable gene (IGHV) in immature B lymphocytes. Aberrant targeting of RAG to non-IGH sites in B cell acute lymphoblastic leukemia (B-ALL) contributes to the development of driver mutations and clonal evolution (Papaemmanuil et al. Nat. Genet. 2014). This finding suggests that patients whose ALL involves increased RAG-mediated clonal diversification would exhibit more aggressive disease. As an initial step toward addressing this hypothesis, we asked whether the extent of RAG-mediated diversification in a patient's leukemia is consistent across all cells or variable between subclones. To assess variation in RAG-mediated subclone diversification, we interrogated rearranged IGH sequences from diagnostic B-ALL specimens to identify early subclones (SC) and to quantify RAG-derived sub-subclones (SSC) from each. We hypothesized that if RAG activity is a consistent feature of the leukemia, all SC within a single patient will have a comparable extent of SSC evolution. Methods: Amplicon-based IGHV sequencing identified the number of clonal IGH SC and their RAG-derived SSC in 22 pre-treatment adult and pediatric patients with newly-diagnosed B-ALL. Analysis was performed on peripheral blood (PB) for all patients in addition to diagnostic bone marrow (BM) for 16 of the 22 patients studied. Ultra-deep sequencing of IGH utilized 500 ng genomic DNA (representing approximately 80,000 cells/specimen) for the MiSeqDx platform, generating ~300 bp reads surrounding the VDJ junctional region. The NCBI IgBlast sequence analysis tool assigned IGH VDJ identities according to germline reference. Methods for determining subclones (SC) of shared clonal lineage involved classifying reads with a common Jh identity and 6 shared upstream Dh-Jh junctional nucleotides (termed "6N_Jx") according to defined methods (Gawad et al. Blood 2012). Further evolved sub-subclones (SCC) - as evidence of ongoing RAG activity - were defined by unique junctional sequences upstream of the common Dh-Jh junction (termed the "NDN" region). SSC were quantified according to their relative proportions within each SC family. Results: VDJ-rearranged SC families were detected for 20 of the 22 patients studied (median 2/patient; range 1-7); further analysis to assess variation in RAG-mediated diversification was limited to the 18 cases with ≥ 2 SC. In 9 of these 18, numerous evolved SSCs were identified from at least one SC in the specimen. In 4/9, there were starkly distinct levels of RAG-mediated diversity observed between intrapatient SC families, with some clonal precursors giving rise to numerous SSCs (up to 2,200 SSC per SC) while others showed minimal-to-no RAG-derived evolution (Table 1). Fifteen of 16 patients with matched BM and PB diagnostic specimens had detectable SCs. Of these, 73% (11/15) shared the dominant SC, while in 27% (4/15) the dominant SC differed between sites. However, regardless of which SC predominated, the extent of SSC diversification within each SC was preserved between the BM and the PB, with similar evolution patterns observed regardless of disease site. There was no relationship between SC read frequency and number of SSCs. Conclusions: Using deep sequencing of a single IGHV locus, wide variation in the extent of subclone diversification was observed in 4 of 20 patients with B-ALL. These findings indicate that the degree of RAG-mediated heterogeneity in B-ALL can range from minimal to extensive among distinct subclones in a single patient. The data underscore the relevance of single cell investigation of tumor characteristics to improving our understanding of the mechanisms of clonal evolution in lymphoid malignancies. Disclosures No relevant conflicts of interest to declare.

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