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PubMed2026

RAS Pathway Activation and Microenvironmental Adaptation as Hallmarks of Myeloid Sarcoma.

UNLABELLED: Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in approximately 20% of patients and remains strikingly understudied in large-scale genomic and multiomic investigations. The key drivers of its tumor evolution are largely unknown; timely detection in asymptomatic patients poses a clinical challenge, and effective treatment options are limited, as patients are often excluded from clinical trials, rendering it a largely neglected disease entity. In this study, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution. This is supported by unique transcriptional signatures of myeloid sarcoma, reflecting adaptation to the extramedullary microenvironment. We establish a proof of concept that circulating tumor DNA (ctDNA) sequencing captures the molecular composition of myeloid sarcoma, offering a potential noninvasive approach for molecular profiling of extramedullary AML. Our findings highlight marked differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as disease hallmarks. SIGNIFICANCE: We provide a comprehensive multiomic characterization of myeloid sarcoma, identifying key molecular pathways that contribute to its development, and suggest ctDNA as a noninvasive method of detection. We identify RAS pathway activation and transcriptional adaptation to the solid tissue microenvironment as cardinal features of myeloid sarcoma, suggesting novel therapeutic avenues.

Sarcoma, Myeloid↗
PubMed1988

Genetic tagging of tumor cells with retrovirus vectors: clonal analysis of tumor growth and metastasis in vivo.

Retrovirus vector infection was used to introduce large numbers of unique genetic markers into tumor cell populations for the purpose of analyzing comparative changes in the clonal composition of metastatic versus that of nonmetastatic tumors during their progressive growth in vivo. The cell lines used were SP1, a nonmetastatic, aneuploid mouse mammary adenocarcinoma, and SP1HU9L, a metastatic variant of SP1. Cells were infected with delta e delta pMoTN, a replication-defective retrovirus vector which possesses the dominant selectable neo gene and crippled long terminal repeats. G418r colonies were obtained at a frequency of 4 x 10(-3). Southern blot analysis of a number of clones provided evidence of random and heritable integration of one or two copies of the proviral DNA. Clonal evolution of primary tumor growth and the nature of lineage relationships among spontaneous metastases and primary tumors were analyzed by subcutaneously injecting 10(5) cells from a pooled mixture of 3.6 x 10(2) G418r SP1HU9L or 10(4) G418r SP1 colonies into syngeneic CBA/J mice. The most striking finding was the relative clonal homogeneity of advanced primary tumors; they invariably consisted of a small number (less than 10) of distinct clones despite the fact that hundreds or thousands of uniquely marked clones had been injected. In the case of the metastatic SP1HU9L cells, the nature of these "dominant" clones varied from one tumor to another. Analysis of a number of lung metastases revealed that a proportion of them were derived from dominant primary tumor clones and were composed of one, and sometimes two, distinct progenitors. In some animals, all the lung metastases were derived from a common progenitor clone, whereas in others, each metastatic nodule had a different progenitor. The results show the following. (i) Retrovirus vector infection can be used to introduce large numbers of unique and stable clonal markers into tumor cell populations. (ii) The progeny of a very limited number of clones dominate in advanced primary tumors. (iii) Mammary carcinoma metastases are of mono- or biclonal origin. The significance of the results is discussed.

Adenocarcinoma↗
PubMed1990

Chromosomal evolution and tumor progression in a myxoid liposarcoma.

A myxoid liposarcoma showed macroscopic, histologic, and cytogenetic heterogeneity. In one of three myxoid nodules and in the surrounding lipoma-like tumor tissue, the translocation t(12;16)(q13;p11), known to be specific for myxoid liposarcoma, was found as the sole chromosomal abnormality. In the other two nodules, additional rearrangements involving chromosomes 1, 12, and 16 were found. These aberrations were probably secondary to the primary t(12;16), and are cytogenetic evidence of clonal evolution. The complex chromosome aberrations were present in those tumor parts that had more malignant histology, indicating that the acquisition of secondary chromosomal aberrations parallels the histologic manifestations of tumor progression.

Chromosome Aberrations↗
PubMed2026

Grade progression and high-grade transformation in neuroendocrine neoplasms.

Epithelial neuroendocrine neoplasms (NENs) comprise a biologically diverse group of malignancies that span a wide spectrum of differentiation, proliferative activity, and clinical behavior. Contemporary classifications distinguish well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinomas (NECs). However, growing longitudinal data indicate that a subset of NETs may undergo temporal evolution characterized by rising Ki-67, increasing morphologic atypia, and acquisition of genomic alterations classically associated with NEC, particularly TP53 and, less commonly, RB1 inactivation. These phenomena, referred to as grade progression and high-grade transformation, can result in tumors with NEC-like behavior despite retention of a NET molecular backbone, creating diagnostic and therapeutic ambiguity. In this review, we synthesize recent evidence on the molecular, morphologic, and clinical features of gastroenteropancreatic NET grade progression and transformation, highlight the role of clonal evolution and treatment-associated selection pressure, and discuss implications for imaging, biopsy strategy, molecular profiling, and therapy selection.

Humans↗
PubMed1992

Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin.

One hundred and seventeen patients with severe aplastic anemia (SAA) were treated at our institution between 1976 and 1990 with antilymphocyte globulin (ALG) therapy. Seventy-nine (68%) are alive and probability of survival at 14 years, according to Kaplan and Meier, is 62% +/- 12%. Twenty-six patients developed a late clonal complication: 11 had a myelodysplastic syndrome (MDS) and 17 had paroxysmal nocturnal hemoglobinuria (PNH); two patients had both. The cumulative risk at 10 years is 42%. The development of MDS/PNH after SAA directly affects survival. The probability of being alive at 14 years is 81% +/- 10% for patients with stable disease and 36% +/- 13% for those with clonal evolution (P = .001). To look for predictive signs, we reevaluated peripheral blood and bone marrow cytomorphology at presentation, during regeneration, and in remission. We examined the peripheral blood values for hemoglobin, reticulocytes, granulocytes, thrombocytes, mean corpuscular volume (MCV), and fetal hemoglobin, as well as bone marrow for cellularity, erythropoiesis, myelopoiesis, and megakaryopoiesis. ALG therapy induces slow and incomplete recovery. Although in "remission," ALG patients have lower hemoglobin values, higher reticulocyte counts, lower granulocyte and platelet values, and a higher MCV and fetal hemoglobin than normal controls. They retain a reduced number of megakaryocytes and a persistence of atypical monocytes in bone marrow morphology as stigmata of their disease. Patients with late clonal complications show distinct morphologic abnormalities: patients with PNH have higher MCVs, higher granulocyte and reticulocyte counts, and more dyserythropoiesis at diagnosis and a lower hemoglobin with an increased proportion of erythroblasts in the bone marrow in "remission." Patients who later developed MDS are not different from the total patient population at diagnosis. After therapy, these patients are characterized by the presence of ring sideroblasts and atypical monocytes during regeneration and by a persistent increase in MCV, a higher fetal hemoglobin, lower granulocyte values, and megakaryocytic dysplasia during "remission." Thus, routine morphologic follow-up examination of blood and bone marrow can discover patients at risk for late hematologic complications after ALG therapy.

Adult↗
PubMed1990

Evolving abundance and clonal pattern of human germinal center B cells during childhood.

Childhood is a critical period for the development of the memory B-lymphocyte repertoire necessary in protective humoral immunity. This study addressed the natural history of memory B cells based on the previous identification of germinal center and mantle zone cells as the probable precursor and mature memory cell populations, respectively. Using flow cytometric quantitation of these B-cell subpopulations in human tonsil, we found that germinal center cells were abundant (70% of tonsil B cells) during early childhood (2 to 3 years), but decline by early adolescence (8 to 14 years) to a low level (33%, P = .0003). To study the clonal evolution of these B-cell subpopulations, germinal center and mantle zone B cells were isolated using a preparative magnetic immunobead method, and analyzed using a novel polymerase chain reaction-based quantitative assay to measure the abundance of B-cell clones bearing certain rearranged VH subfamilies. Two VH subfamilies were informative: VH1N clones were uniquely deficient in germinal center B cells at the early age period, but became abundant in later childhood; and VH3L clones were absent among germinal center cells regardless of age. In contrast, B-cell clones bearing each VH subfamily were abundant in the mantle zone subpopulation throughout childhood. These findings suggest that the abundance and clonal pattern of germinal center B cells evolves during childhood, presumably due to changing antigenic or ontogenic processes. Moreover, the distinct clonal pattern of germinal center versus mantle zone B cells suggests that a major phase of clonal selection occurs after germinal center emigration.

Adolescent↗
PubMed1992

Cytogenetic analysis in the diagnosis of acute leukemia.

Acute leukemias are characterized by acquired genetic rearrangements that, in most cases, can be detected by cytogenetic methods as clonal chromosomal abnormalities. Whereas primary abnormalities contribute to the establishment of the leukemia and often are seen as solitary changes, secondary aberrations accrue during clonal evolution. Both abnormalities are nonrandom in distribution. The pattern differs between acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) and from subtype to subtype. Some abnormalities are so characteristic as to be virtually pathognomonic for particular types of leukemia. The importance of cytogenetic characterization of leukemias is thus two-fold. First, the recurrent aberrations provide insight into the pathogenetic mechanisms that are operative. They pinpoint areas of the human genome that carry genes or regulatory sequences whose function is disrupted in neoplastic cells. Second, even before the long-term goal of a more fundamental understanding of the neoplastic process is reached, the cytogenetic aberrations have direct clinical importance. The finding of an acquired clonal chromosomal abnormality in hematopoietic cells identifies the presence of a neoplastic disease. The aberration profile may reveal whether the patient has ALL or ANLL and which subtype it is. Remission and relapse can be monitored by cytogenetic analyses. Finally, the karyotypic pattern is an independent prognostic parameter that should be considered when the choice of therapy is made.

Chromosome Aberrations↗
PubMed1990

Chromosome analysis of 31 Wilms' tumors.

Cytogenetic analysis was done on 31 Wilms' tumors, including 2 renal tumors of clear cell sarcoma type, using short term cultures of primary tumors and/or nude mouse passages. Nonrandom secondary chromosome abnormalities, in particular, were noted as evidence of clonal evolution. Apparently normal karyotypes were found in 5 Wilms' tumors, all in patients less than or equal to 22 months old, and in one clear cell sarcoma. Abnormal karyotypes were seen in 25 tumors (80%); 6 were pseudodiploid, 3 were hypodiploid, and 16 (52%) were hyperdiploid, of which 8 had a modal number of 47-49 and 8 had a modal number of 50-55. Nonrandom structural abnormalities involved 1p/1q, 11p, 7p/7q, 16p/16q, 12q, and 17p/17q. Nonrandom numerical abnormalities included +6, +8, and +18. Trisomy 12 was the most common abnormality, structural or numerical, seen in 52% of tumors (81% of the hyperdiploid). In 2 tumors the +12 was the only apparent abnormality; in 1 other tumor an i(12q) was seen, suggesting that +12 may have special significance in the clonal progression of Wilms' tumor. Informative karyotypes of 68 Wilms' tumors from other reports were reviewed and compared to results in this series.

Child↗
PubMed1990

Cytogenetics in the investigation of haematological disorders.

Chronic and acute, myeloid and lymphatic haematological neoplasms are characterized by acquired genetic rearrangements that, in the majority of cases, can be detected as clonal chromosomal abnormalities. The aberrations are either primary, meaning that they contribute to the establishment of the neoplasm, or secondary, in which case they are acquired during the clonal evolution and malignization of the neoplastic cells. The abnormalities are non-randomly distributed; the aberration pattern differs from disease to disease and sometimes is so characteristic that individual rearrangements may be virtually pathognomonic for particular neoplasms. The cytogenetic characterization of haematological malignancies is of two-fold importance. First, the recurrent aberrations provide us with an insight into the pathogenetic mechanisms that are operative. They pinpoint those areas of the human genome that carry genes or regulatory sequences whose function is disturbed in leukaemias and lymphomas. Using DNA recombinant techniques in addition to chromosome-level investigations of these cancer-associated rearrangements, the molecular pathology of leukaemias and lymphomas is now gradually being unravelled. Second, even before the long-term goal of a more fundamental understanding of the neoplastic process is reached, the cytogenetic aberrations have a direct clinical importance. The finding of an acquired, clonal chromosome abnormality in haematopoietic cells (-Y in old men is an exception) means that the patient has a neoplastic disease. Often, but by no means always, the type of aberration is also informative as to which type of neoplasm is present. During therapy, remission and relapse can be monitored by cytogenetic analyses. Finally, the karyotypic pattern influences prognosis and may thus be taken into account when the choice of therapy is made.

Chromosome Aberrations↗
PubMed1991

Evidence for clonal disease by magnetic resonance imaging in patients with hypoplastic marrow disorders.

Some patients with hypoplastic marrow disorders, including aplastic anemia (AA), are at risk for clonal evolution to myelodysplastic syndromes (MDS) and leukemia. Magnetic resonance imaging (MRI) of marrow of the spine, pelvis, and femurs was performed in 24 patients with hypoplastic marrow disorders. In 12 patients (three AA, nine MDS) MRI was compatible with the clinical and biopsy diagnoses and served to define the spectrum of marrow patterns in these disorders. In eight patients with hypocellular marrow biopsies and a clinical diagnosis of AA, MRI showed an unexpected inhomogeneous or diffuse cellular pattern. Concurrent or subsequent marrow or cytogenetic studies have led to diagnoses of hypoplastic MDS in seven of these patients. In four patients with prolonged hypoplasia after bone marrow transplantation for lymphoma, a speckled pattern superimposed on a fatty background appeared in serial MRI studies. One case evolved to AML, two developed megaloblastic foci, and one remains hypoplastic at 19 months. This study suggests that MRI is able to detect early clonal disease in patients with AA, and can distinguish AA from hypoplastic MDS.

Adult↗
PubMed1988

Clonal changes in tumours during growth and progression evaluated by southern gel analysis of random integrations of foreign DNA.

We have exploited random integrations of foreign DNA as a means of genetically tagging tumour cell populations with which to analyse the clonal evolution of tumour growth in vivo. Transfection of a non-metastatic mouse mammary carcinoma called SP1 (or a metastatic variant, SP1HU9L) with the pSV2neo plasmid or retrovirus vector infection with a "clipped-wing' vector (delta p delta eMoTN) was used to generate large numbers of uniquely marked tumour cell clones in single-step selections. The basic approach was to pool large numbers of independently marked transfectants or infectants, inject these cells into mice and analyse the resulting primary tumours and/or metastases later. Overgrowth or derivation of tumour masses by a limited number of clones could be detected by Southern gel analysis. The main findings were: (i) injection of pooled populations containing large numbers of uniquely marked cell clones (up to several thousand) invariably resulted in advanced primary tumours that contained a very limited number of clones, and in some cases only one easily detectable clone; (ii) primary tumours could be overgrown within six weeks by the progeny of the same single metastatic clone when the inoculum contained 1-10% metastatic cells, which suggests that metastatic SP1 cells have a selective growth advantage in primary tumours as well as for metastatic spread; and (iii) spontaneous lung metastases were clonal or biclonal at the time of analysis. The results show that spontaneous metastases can develop from a genetically distinct subpopulation of cells in a non-random (i.e. selective) manner. Because primary tumours can become overgrown by the progeny of a metastatic clone, results of any comparison of the properties of a primary tumour with a distant metastasis could be affected by the stage at which the primary tumour is removed and analysed.

Animals↗
PubMed2026

Overcoming cancer resistance in pancreatic cancer: toward dynamic precision oncology.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, largely because of its profound and evolving therapeutic resistance. Resistance is not determined by a single molecular alteration but arises from interconnected mechanisms, including intrinsic resistance, treatment-induced adaptive resistance, acquired resistance, genomic evolution, clonal selection, cancer stemness, phenotypic plasticity, metabolic adaptation, and tumor microenvironment-mediated effects. Emerging therapeutic approaches targeting KRAS/RAS signaling, stromal and immune components, metabolic dependencies, and DNA damage repair pathways offer opportunities to address these mechanisms, although durable efficacy remains limited by biological heterogeneity and adaptive responses. In this review, we examine therapeutic resistance as an evolutionary and multidimensional process and summarize emerging strategies for overcoming resistance. We further propose a Dynamic Precision Oncology (DPO) framework that extends conventional precision oncology beyond baseline molecular profiling by integrating longitudinal assessment of tumor genomics, circulating tumor DNA, CA19-9, imaging, radiomics, and clinical characteristics. This framework emphasizes iterative detection and characterization of emerging resistance, mechanism-informed treatment adaptation, and subsequent reassessment rather than automatic treatment modification based on a single biomarker. DPO may provide a conceptual framework for integrating evolving tumor biology into treatment decision-making, while prospective studies are needed to validate biomarkers, define actionable thresholds, and determine whether longitudinal resistance-guided strategies improve clinical outcomes in PDAC.

Humans↗
PubMed1986

Histology and DNA contents of a secondary malignancy arising in a mature residual lesion six years after chemotherapy for a disseminated nonseminomatous testicular tumor.

The current report describes a secondary malignancy developing in a retroperitoneal mature residual lesion 6 years after chemotherapeutic treatment of a disseminated nonseminomatous testicular tumor. The histologically malignant component was not present in the primary tumor and consisted of polygonal and fusiform cells with focal tubular formations, resembling primitive neuroectodermal tissue. Immunoperoxidase staining for alpha-fetoprotein and the beta-subunit of human chorionic gonadotropin remained negative, whereas focal positivity for S100 protein was observed. Neuron specific enolase positivity was equivocal. The DNA contents of both the mature components in the primary and the metastatic retroperitoneal tumor and in the various malignant components of the primary tumor, were in the hypotriploid range. In the malignant component of the retroperitoneal metastasis, a hypertriploid peak was observed. These findings suggest further clonal evolution in a phenotypically mature, genotypically abnormal residual metastatic tumor after chemotherapy. It is stressed that the mature appearance of the residual lesions may be deceiving and that these lesions are highly susceptible to resume malignant behavior.

Adult↗
PubMed1986

Balanced and unbalanced 1;19 translocation-associated acute lymphoblastic leukemias.

The authors studied clinical and immunologic characteristics of six children with 1;19 translocation-associated acute lymphoblastic leukemia (ALL); two of the six had the balanced type, t(1;19)(q23;p13), three had the unbalanced type, -19,+der(19)t(1;19)(q23;p13) with a resultant partial 1q trisomy, and the other had a mosaicism of cells with the balanced type and those with the unbalanced one, t(1;19)/-19,+der(19)t(1;19). Leukemic cells of all three patients, in which intracytoplasmic immunoglobulin was determined, were proved to show pre-B phenotype. Of the six patients, three had an initial leukocyte count of greater than 50 X 10(9)/l, and were classified in the high-risk group. Three patients relapsed after a brief remission and died. The mosaicism observed suggested that at least in some patients the leukemic cells with -19,+der(19)t(1;19) might derive from those with t(1;19) as a step in the course of clonal evolution. Our data and a review of the literature indicate that there may be no differences in the clinical and immunologic characteristics between the patients with the balanced translocation and those with the unbalanced one, and that the leukemia with the 1;19 translocation may join with other translocation-associated ALLs, with which the patients are known to have poor prognosis.

Adolescent↗
PubMed1987

Clinical and prognostic features of patients with Philadelphia chromosome-positive chronic myelogenous leukemia and extramedullary disease.

Twenty-four patients who developed extramedullary disease during the course of Philadelphia chromosome-positive chronic myelogenous leukemia are described. The most frequent sites of extramedullary disease were lymph nodes (54%), bone (37%), and skin and soft tissue (29%). The appearance of extramedullary disease was associated with a high incidence of other features of accelerated disease (37%) and with cytogenetic clonal evolution (62.5%). The median time from extramedullary disease to blastic crisis was 4 months, and the median survival was 5 months. At the time of analysis, 23 patients have died, 16 after evolving into blastic crisis, and 7 from progressive disease without satisfying the criteria of medullary blastic crisis. This study confirms the importance of extramedullary disease as a sign of poor prognosis in chronic myelogenous leukemia, and the need for alternate therapies when such an event develops.

Bone Neoplasms↗
PubMed1989

Acute transformation of chronic large granular lymphocyte leukemia associated with additional chromosome abnormality.

A patient with large granular lymphocyte (LGL) leukemia that transformed into an acute or aggressive form after 20 months of the chronic phase is reported. The patient's leukemic cells were mature, medium-sized lymphocytes with sparse azurophil granules and the surface phenotypes of the cells were CD2+, CD3-, CD11+, and CD16+. Molecular analysis showed a germ line configuration in both T-cell receptor beta-chain genes and T-cell receptor tau-chain genes. A clonal anomaly of chromosome (trisomy 8) was demonstrated in peripheral blood cells. LGL after acute transformation of the disease displayed large blastic morphology with prominent nucleoli, intense basophilic cytoplasm, and numerous granules. Karyotypic analysis demonstrated a mosaic of trisomy 8 and trisomy 8 with an additional marker chromosome. Thus, transformation of chronic LGL leukemia into an acute or aggressive form in this patient was associated with morphologic and karyotypic changes of the leukemic cells. Patients with a stable form of chronic LGL leukemia should be examined carefully for the possible acute crisis associated with a clonal evolution.

Adult↗
PubMed1990

Blastic transformation in essential thrombocythemia. In vitro differentiation of blast cells into granulocytic, erythroid, and megakaryocytic lineages.

A 57-year-old man with essential thrombocythemia (ET) developed myelofibrosis, that progressed to a blastic transformation state. The characteristics of the blastic cells were serially studied both morphologically and phenotypically as well as in cell culture. The blastic cells that were first detected in peripheral blood had features of myeloid stem cells with slight differentiation toward megakaryocytic lineage. However, later in the course, most of the blastic cells were immature. During culture in the presence of human plasma-derived serum (PDS), some blastic cells obtained at the initial stage differentiated, mainly to both granulocytes and macrophages morphologically, but later tended to differentiate into both megakaryocytes and macrophages. Finally the blasts appeared to have lost their ability to differentiate morphologically. However, the blasts formed mixed colonies consisting of erythroblasts, granulocytes, macrophages, and immature blasts when cultured in methylcellulose with PHA-leukocyte conditioned medium. In addition, the blastic cells in suspension culture strongly expressed phenotypic features which are characteristic of erythroblasts, in the presence of both PDS and 12-0-tetradecanoylphorbol 13-acetate (TPA), whereas they expressed features of megakaryoblasts in the presence of PDS alone. These results suggest that essential thrombocythemia is of myeloid stem cell origin. This is the first case in the literature in which a clonal evolution in ET has been followed closely, essential events were identified serially, and the blastic cells, which appeared as a result of the progression of ET, were found to have the capability to differentiate toward the three myeloid lineages.

Blast Crisis↗
PubMed1976

Long-term cytogenetic studies in acute leukemia of children; the nature of relapse.

Sequential long-term cytogenetic studies in 71 children with acute leukemia were designed to investigate the nature of relapse after prolonged remission. In the overwhelming majority of the cases the findings suggested clonal identity of the leukemic cell population in relapse with that studied at the onset of the disease, notwithstanding considerable karyotypic instability in almost half of the patients. In a small minority an independent origin of the relapse clone could not be excluded on cytogenetic grounds but was considered unlikely, since mechanisms capable of accounting for the changes observed in these patients could be demonstrated in other cases. The persistence of diploid leukemic cells in the presence of an aneuploid subclone was demonstrated in the relapse bone marrow and/or spinal fluid in all active phases of the disease. On this basis the conversion from an aneuploid to a predominantly or exclusively diploid karyotype could be visualized, and a new model of clonal evolution, involving repetitive formation of abnormal karyotypes from a surviving diploid clone could be suggested.

Adolescent↗