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At least 19 recordsLinked to original sources
PubMed2026

Genetic Profile, Treatment Response, and Outcomes of BCR::ABL1-Positive Mixed-Phenotype Acute Leukemia: A Study From the BCR::ABL1 Pathology Group.

Mixed-phenotype acute leukemia (MPAL) with BCR::ABL1 fusion is rare, and its clinicopathological features, genetic landscape, therapeutic response, and patient outcomes remain incompletely defined, as does its relationship to blast-phase chronic myeloid leukemia. In this multicenter study of 44 patients, 86.4% had B/myeloid MPAL, 72.7% showed lymphoid predominance, 40.9% had complex karyotypes, and 68.3% harbored somatic mutations, most commonly RUNX1 mutations (46.3%). RUNX1 mutations frequently co-occurred with acute myeloid leukemia (AML)-associated alterations, whereas DNMT3A, TET2, and BCORL1 mutations were restricted to RUNX1-mutated cases. In contrast, acute lymphoblastic leukemia (ALL)-associated alterations (IKZF1 mutation/deletion and ETV6 mutations) were confined to RUNX1-wild-type patients. TP53 and signaling pathway mutations (NRAS, KRAS, PTPN11, and FLT3) were not detected. Forty-two patients received induction chemotherapy and/or immunotherapy combined with tyrosine kinase inhibitors: 74.2% of lymphoid-predominant patients and 63.6% of myeloid-predominant patients received ALL- and AML-type therapies, respectively. Ten patients relapsed, and 2 had primary refractory disease; some exhibited a dynamic shift in predominant lineage immunophenotype, chromosomal alterations, and somatic mutations at the relapse or refractory stage. The overall remission rate was 86.8%, with no significant differences across ALL-, AML-, or hybrid-type regimens. After a median follow-up of 24.2 months, the median overall survival was 52.5 months. Complex karyotype was associated with inferior overall survival compared with cases lacking additional chromosomal alterations (P = .02), whereas RUNX1 mutations were not. No significant differences in genetic profiles, treatment response, or outcomes were observed between patients with and without chronic myeloid leukemia-like features. This study provides a comprehensive genomic and clinical characterization of BCR::ABL1-positive MPAL, supporting improved risk stratification and future therapeutic strategies.

Adolescent↗
PubMed2024

Genetic evidence for predisposition to acute leukemias due to a missense mutation (p.Ser518Arg) in ZAP70 kinase: a case-control study.

BACKGROUND: The apparent lack of additional missense mutations data on mixed-phenotype leukemia is noteworthy. Single amino acid substitution by these non-synonymous single nucleotide variations can be related to many pathological conditions and may influence susceptibility to disease. This case-control study aimed to unravel whether the ZAP70 missense variant (rs104893674 (C > A)) underpinning mixed-phenotype leukemia. METHODS: The rs104893674 was genotyped in clients who were mixed-phenotype acute leukemia-, acute lymphoblastic leukemia- and acute myeloid leukemia-positive and matched healthy controls, which have been referred to all major urban hospitals from multiple provinces of country- wide, IRAN, from February 11' 2019 to June 10' 2023, by amplification refractory mutation system-polymerase chain reaction method. Direct sequencing for rs104893674 of the ZAP70 gene was performed in a 3130 Genetic Analyzer. RESULTS: We found that the AC genotype of individuals with A allele at this polymorphic site (heterozygous variant-type) contribute to the genetic susceptibility to acute leukemia of both forms, acute myeloid leukemia and acute lymphoblastic leukemia as well as with a mixed phenotype. In other words, the ZAP70 missense variant (rs104893674 (C > A)) increases susceptibility of distinct cell populations of different (myeloid and lymphoid) lineages to exhibiting cancer phenotype. The results were all consistent with genotype data obtained using a direct DNA sequencing technique. CONCLUSION: Of special interest are pathogenic missense mutations, since they generate variants that cause specific molecular phenotypes through protein destabilization. Overall, we discovered that the rs104893674 (C > A) variant chance in causing mixed-phenotype leukemia is relatively high.

Humans↗
PubMed2026

BCL11B enhancer hijacking by t(14;16)(q32;q24) translocation defines a novel high-risk subtype of T-ALL.

The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cisregulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed-phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2 and activating epithelial-mesenchymal transition transcription signatures. Immunophenotypic and single-cell RNA sequencing analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34+ cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15% to 4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults. Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.

Humans↗
PubMed1985

Simultaneous or sequential expression of lymphoid and myeloid phenotypes in acute leukemia.

Acute mixed myeloid-lymphoid leukemia is uncommon. We report four cases in which myeloid and lymphoid cell markers were observed simultaneously or sequentially when 94 patients with acute leukemia were phenotyped according to the French-American-British (FAB) classification system, with cytochemical stains, and with immunologically defined differentiation markers (identified by monoclonal antibodies and antiterminal deoxynucleotidyl transferase [TdT]). In one case, conversion from acute lymphoblastic leukemia to acute myeloid leukemia was noted (FAB L1, TdT+ to FAB M4, Auer rods, TdT-). In another patient, two distinct populations of myeloid and lymphoid blast cells were observed simultaneously (TdT-, LeuM1+/TdT+, LeuM1-). In two additional patients, acute leukemia was characterized by the expression of both lymphoid and myeloid markers on the same cell (TdT+/Leu M1+, B4+/Leu M1+ and greater than or equal to 70% TdT+, T11+, My9+). The Philadelphia (Ph1) chromosome was negative in all cases, though other chromosomal abnormalities were noted in three out of four cases. Malignant transformation of a pluripotential stem cell for both lymphoid and myeloid lineages, with or without the Ph1 chromosome marker, could explain the coexistence of distinct populations of lymphoblasts and myeloblasts in acute leukemia. Acute leukemia with a biphenotypic profile may reflect genome depression accompanying neoplasia.

Adult↗
PubMed1988

Tetraploidy and Y chromosome loss in acute mixed-lineage leukemia.

An unusual case of acute leukemia with mixed phenotype was followed up from diagnosis to death for about 12 months. The first cytogenetic examination revealed about 80% of the bone marrow cells in the diploid and 20% in the tetraploid range. After two courses of induction therapy, complete remission was achieved within 2 months. At this time the tetraploid cells were reduced to 3%, but 50% of the mitoses showed a Y chromosome loss, while the other mitoses had a diploid karyotype. Early intensification therapy was given 6 weeks later with slow recovery of blood counts. After four months a sharp decrease of the number of Y-missing mitoses was observed, while the marrow remained in full remission. Two months later a relapse occurred and the patient died. At this time the -Y clone had dropped to 2% and the tetraploid clone was totally absent. We conclude from these findings that the diploid clone was the most malignant one, whereas the -Y cells were probably not directly involved in the leukemic process.

Chromosome Banding↗
PubMed1990

Clinical features and biological implications of acute mixed lineage (hybrid) leukemias.

The composite phenotype of a population of leukemic blast cells is derived through analysis of morphology, cytochemistry, cytogenetics, surface antigens, and gene structure. When analyzed in such a fashion, approximately 10-25% of childhood acute leukemias will show markers of more than one lineage; these may be coexpressed on individual cells (biphenotypic) or appear on two distinct blast populations (bilineal or biclonal). Occasionally, there is conversion from one leukemic phenotype at diagnosis to another phenotype at relapse (lineage shift). Mixed lineage features appear to have biologic and prognostic significance. Some specific mixed lineage leukemia syndromes have been identified; among them are acute nonlymphoid leukemia with T-lymphoid features, CD7+, CD4-, CD8- acute leukemia, CD2+/CD19+ acute lymphoid leukemia, and acute leukemias associated with specific cytogenetic markers, e.g., t(4;11) and t(9;22). In general, these forms of acute leukemia along with others with mixed lineage markers have a poor prognosis, and new therapeutic approaches appear to be indicated.

Antigens, Differentiation↗
PubMed1993

Mixed acute leukemia with genotypic lineage switch: a case report.

Morphologically well classifiable leukemias can reveal a mixed phenotype. A case of acute myeloid leukemia (CD13, CD33, CD14, CD11b) which at presentation showed a co-expression of B-lymphoid markers (CD19, CD10, CD20), at the time of the first relapse revealed a morphologic, phenotypic and genotypic switch of the blasts to a purely lymphoid form. Analysis of the immunoglobulin (Ig) H chain locus and of the T-cell receptor (TCR) genes showed at diagnosis a germline configuration of the IgH, TCR beta and tau genes, and a deletion of the TCR delta gene at the second chromosome. At relapse, monoclonal rearrangements of the IgH, TCR tau, and TCR delta were detected. At a subsequent relapse, the blasts re-expressed myeloid morphologic features and myeloid-associated antigens, while they retained the same rearranged configuration of the IgH and TCR beta and delta genes. The TCR delta gene configuration, which links each phase of the disease, may represent an early pathogenetic event and makes the emergence of a second malignancy unlikely. Each phenotypic change occurred after anti-myeloid and anti-lymphoid oriented chemotherapy. The close correlation between the progressive acquisition of different phenotypes and the switch at the genomic level represent the peculiar features of this unusual case.

Adult↗
PubMed1991

Review of the incidence and clinical relevance of myeloid antigen-positive acute lymphoblastic leukemia.

An increasing number of papers document cases of acute leukemia in which individual blast cells co-express markers normally restricted to a single cell lineage. Numerous terms are used to refer to cases with unscheduled expression of lineage-foreign proteins; the best defined categories were hybrid acute leukemia and acute mixed-lineage leukemia. The incidence of phenotypically variant acute leukemia varies with the quality and quantity of parameters used and the stringency of the criteria employed for its definition. Considerable interest has focused on acute lymphoblastic leukemia (ALL) cells expressing one or several myeloid lineage-associated antigens (My+ ALL), CD13, CD14, CD15, CD33, and CDw65. Owing to legitimate and cryptic expression on lymphoid cells, CD11b and CD15 reagents may not be considered as specific indicators of myeloid differentiation. The reported incidence ranged from 5 to 46% in 14 studies on My+ ALL, totalling 3817 patients. Several detailed reports documented a higher incidence of My+ ALL in adults (realistically in the range 10-20%) than in children (5-10%) and in B-lineage ALL as opposed to T-lineage ALL. My+ ALL cases are more likely to display unique cytogenetic [t(9;22), 11q23, 14q32] features than My-neg ALL. There appears to be no predominant expression of a single myeloid-associated antigen among those analyzed. As the morphological diagnosis of a leukemia subtype is often imprecise, some T-neg B-neg My+ ALL cases might actually contain FAB AML-M0 populations. While the expression of myeloid-associated antigens has no apparent prognostic significance in the majority of childhood ALL subtypes, in adults myeloid antigens seem to identify a high risk group of ALL patients with a poorer response to standard ALL therapy.

Adult↗
PubMed1988

Mixed-lineage leukemias and phenotypic shifts occurring in relapsed cases of acute T lymphoblastic lymphomas.

Specimens from 19 patients with NHL were also phenotyped at the onset of the disease; among them, 9 were studied in the relapse phase. The analysis was carried out with monoclonal antibodies directed against T and myeloid cells; at diagnosis, all cases presented an immature thymic phenotype. When analyzed at relapse, phenotypic changes were observed: intra-lineage dedifferentiations (6 cases); mixed-lineage lymphoid and myeloid (2 cases), and pure myeloid relapses (1 case). The molecular analysis of the TCR-genes configuration showed a germ-line pattern at onset and relapse in Case 9 and a modification of the rearrangement patterns during the evolution of the disease in Case 6. These data point out that the relapse is often accompanied by intra-lineage modifications resembling dedifferentiation and, more rarely by a myeloid switch. The phenotypic follow-up of these patients may be important to the implementation of chemotherapeutic protocols that are more adequate for the biological evolution of the disease.

Antibodies, Monoclonal↗
PubMed1991

Associated leukemia and mixed germ cell tumor in a patient with gonadal dysgenesis.

A 16-year-old phenotypic female developed acute myeloblastic leukemia with a fulminant course very shortly after surgery and chemotherapy for a mixed germ cell tumor of the ovary. The karyotype (46, XY, 47, XY + 8) suggested de novo rather than therapy-associated leukemia. The relationship between germ cell tumors and leukemia, their common yolk sac derivation and the role of the Y chromosome are discussed. The idea that XY gonadal dysgenesis may be familial also is discussed.

Adolescent↗
PubMed1991

[An autopsy case of acute mixed lineage leukemia with monosomy 7 in a child].

A five-year-old boy initially diagnosed common ALL was developed to acute myelomonocytic leukemia. At onset, the bone marrow was hypercellular and 77% of the cells were blasts, mainly lymphoblast-like cells and cytogenetic study demonstrated 45, XY, -7 in all blasts. Cytochemically most of those blasts were negative for peroxidase, sudan black B, alpha-NB esterase staining. The immunological phenotype was J5 (CD10)+, I2 (HLA-DR)+, SmIg-, CyIgmu-, Leu1 (CD5)-, OKT11 (CD2)-, MY7 (CD13)-, suggesting common ALL. Eight months later, the bone marrow cells were occupied with large sized blasts which were almost positive for peroxidase stain and the cells showed coexpression of Mo1 (CD11b)+, MY4 (CD14)+, MY7+, MY9 (CD33)+, MCS2 (CD13)+, I2+, J5-, B4 (CD19)-, Mo2 (CDw14)-, at relapse. He died 2 years and 6 months after his initial diagnosis. An autopsy was performed which revealed generalized infiltration of leukemic cells and aspergillosis of the lung. In general, monosomy 7 is associated with myelodysplastic syndrome in childhood, and is terminated to acute myeloblastic leukemia. In this case, bone marrow blasts demonstrated monosomy 7 cytogenetically, and this case was considered as an acute mixed lineage leukemia of bilineal type. And this case proved that a monosomy 7 can also be terminated to acute mixed lineage leukemia with both lymphoid and myeloid phenotypes.

Child, Preschool↗
PubMed1994

Flow cytometric detection of residual disease in acute leukemia by assaying blasts co-expressing myeloid and lymphatic antigens.

A method employing CD45-gating of blast cells was evaluated for the flow cytometric detection of residual disease in CD19- and myeloid antigen-positive acute leukemia in morphologic remission. In the normal bone marrow, CD45-gating identified at least three populations of immature cells, one of which appeared to retain a minute fraction of CD19- and CD13/33-antigen co-expressing cells. In acute leukemia, CD45 expression separated the blast cell population from the normal marrow cell populations. In the majority of patients with CD19- and myeloid antigen-positive acute leukemia, subpopulations of blast cells with this mixed phenotype were detected during morphologic remission.

Antigens, CD↗
PubMed1990

Biphenotypic acute leukemia in adults.

Leukemias are characterized by an idiopathic proliferation of a progenitor cell that is committed to a single cell lineage. However, leukemias with dual-lineage differentiation are being described, especially within the pediatric age group. The authors reviewed 118 cases of adult acute leukemia phenotyped by immunofluorescent flow cytometry; 7 cases demonstrated mixed cell lineage. Immunophenotypically these cases were defined by early B-lymphocyte differentiation (TdT, HLA-DR, and CD19) coexpressed with a myeloid receptor (CD13, CD15, or CD33) on the same leukemic cell. Routine cytochemical evaluation demonstrated punctate positivity of the blasts with naphthol AS-D chloroacetate esterase stain in five of seven cases. Cytogenetic analysis revealed structural abnormalities of chromosome 11 in four of the seven cases. Three of these studies showed a break at 11q23-24, the location of the human proto-oncogene ets-1. Clinically, two of these leukemias represented chronic myelogenous leukemia in blast crisis, and all cases behaved aggressively. The authors' data suggest that mixed lineage leukemias are an identifiable subset of adult acute leukemias and are associated with a poor prognosis.

Acute Disease↗
PubMed1988

Immunophenotyping in the diagnosis and classification of acute lymphoblastic leukemia.

The identification of ALL immunophenotypes with distinctive clinical features and prognostic significance indicates the importance of these studies in the evaluation of ALL patients for both clinical and research purposes. For differential diagnosis, the expression of pan-B-cell or pan-T-cell lymphoid antigens and the absence of myeloid/monocyte antigens represent the most useful markers for distinguishing ALL from AML. However, the increasing appreciation of large numbers of patients with clinically significant mixed lymphoid-myeloid phenotypes suggests that rigid classification of acute leukemias into exclusive lymphoid and myeloid categories may be somewhat artificial. In adult ALL, patients with My+ phenotypes (B+sIg-T-My+ and B-sIg-T-My+) have a lower incidence of complete remission and shorter survival times than do patients with My- marker profiles. Preliminary studies in childhood ALL also suggest a correlation between myeloid antigen expression and poor prognostic factors. In addition, children with sIg+ "B-cell," cIg+ "pre-B-cell," and T-cell ALL phenotypes have shorter disease-free survival times than do patients with more common "early pre-B" (B+cIg-sIg-T-) marker profiles. Application of immunologic markers in concert with cytogenetic and gene rearrangement studies has led to the identification of novel subgroups of leukemia with distinct clinical characteristics. Future studies incorporating a multiparameter diagnostic approach including immunophenotyping, gene rearrangement studies, and karyotypic analyses should further our understanding of the heterogeneity of acute leukemias, guide the development of new therapeutic strategies, and provide for more clinically relevant classification of these disorders.

Antibodies, Monoclonal↗
PubMed2002

Flow cytometric characterization of phenotype, DNA indices and p53 gene expression in 55 cases of acute leukemia.

OBJECTIVE: To characterize the phenotype of acute leukemia cases using flow cytometry, to detect mixed lineage cases and to use DNA index determination, including S-phase fraction (SPF) and p53 detection, to find if there was any correlation of SPF and p53 expression with outcome. STUDY DESIGN: Fifty-five cases of acute leukemia were enrolled in this study. A complete hemogram and routine bone marrow examination, including cytochemistry, was done. Mycloperoxidase-negative cases were evaluated on a flow cytometer using monoclonal antibodies. DNA indices were determined by flow cytometry in all cases, and p53 was detected immunohistochemically using the alkaline phosphatase/antialkaline phosphatase technique. RESULTS: Acute myeloblastic leukemia (AML) was diagnosed in 32 cases; acute lymphoblastic leukemia (ALL) was diagnosed in 18 (14 B lineage and 4 T line age). Four cases showed mixed lineage leukemia, and undifferentiated acute leukemia was diagnosed in one case. The mean/range of SPF for these groups were 3.76/0.33-6.91, 6.25/0.15-21.4, 2.89/0.35-10.64, 2.60/0.72-6.94 and 7.34, respectively. Aneuploidy was detected in two cases of B-lineage ALL and tetraploidy in a case of AML-M7, while all others were diploid p53. Was detected in 6 of 55 cases (10.90%). Follow-up was available for 24 patients. Five patients relapsed, and four had B-cell type ALL and were diploid and expressed no p53 gene. SPF% did not show any correlation with outcome. CONCLUSION: These data suggest that within acute leukemia subtypes, there is a wide variation in SPF. SPF does not seem to correlate with outcome. Immunophenotyping is essential to determine the lineage in myeloperoxidase-negative cases. It is perhaps the only way to diagnose mixed lineage leukemia and aberrant expression of markers presently. The p53 gene was detected less frequently. However, more studies are required from different centers with longer follow-up to evaluate prognostic significance.

Adolescent↗