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PubMed1990

[Mixed blast crisis with the cytogenetic evidence of three clonal evolutions].

A 46-year-old man was diagnosed as having chronic myelogenous leukemia (CML) in chronic phase in Dec. 1985. In Dec. 1987, anemia and leukocytopenia progressed, and the percentage of blast cells increased in the bone marrow. The blast cells were lymphoblastoid and positive for TdT. It was treated as a lymphoid crisis with vincristine and prednisolone, and complete remission was achieved. However, the blasts (11%) were observed in the bone marrow in Mar. 1988, and the chromosomal analysis revealed 46, XY, t (2q-; 11q+), t (9q+; 22q-) in 13 out of 20 cells. In June, the percentage of the blasts increased again, but chromosomal analysis showed a different karyotype, 46, XY, t(2p-; 11p+), t(9q+; 22q-) which was observed in 9 out of 10 cells. Then, myeloblastoid cells increased rapidly in spite of the chemotherapy in Dec. 1988. The chromosomal analysis showed 46, XY, 2p-, 7q-, 9q+, 11p+, 22q- in all analyzed cells. The rearrangement of the bcr gene could be detected by the Southern blotting. The blasts were positive for CD7, CD11, CD13, CD33, CD36, CD41 and CD42, suggesting that the blasts had the surface phenotypes of both myeloid and megakaryocytoid-lineage. This is a case with the mixed blast crisis that changed from the lymphoid to the myelo-megakaryocytoid in nature, in which three clonal evolutions were observed during the clinical course.

Antigens, CD↗
PubMed1977

Cytogenetic evidence of clonal evolution in 5q- anemia.

The clinical homogeneity of myeloproliferative syndromes associated with a 5 q- marker can be contested, but nevertheless finds support in the 2 case reports we have cited. One of these observations of refractory anemia with partial myeloblastosis and 5 q- marker has shown a transformation into an acute myelomonocytic leukemia with clonal chromosomal evolution.

Aged↗
PubMed2025

Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism.

NLRP3 mosaicism is a well-established mechanism causing the monogenic autoinflammatory disease named cryopyrin-associated periodic syndromes (CAPS). The number of reported patients with NLRP3 mosaicism is small, and the knowledge about the long-term disease behavior is limited. Herein we assembled the largest cohort of individuals with NLRP3 mosaicism reported to date to obtain additional evidence that strengthens the understanding of this disease. The novel genetic data were obtained by using Sanger and next-generation sequencing methods, whereas in vitro analyses determined the functional consequences of detected variants. A total of seventeen individuals with NLRP3 mosaicism were enrolled, with 16/17 experiencing different CAPS phenotypes. An overrepresentation of late-onset forms was detected (37.5%). Overall, clinical manifestations, analytical results, and outcomes of treatments were markedly similar to those detected in patients with germline variants. A large mutational diversity was identified, with 16 different variants among 17 individuals. Two main patterns of mosaicism (extended vs. myeloid-restricted) were detected, with the last one overrepresented in the late-onset group. The evaluation of mosaicism over time identified three different patterns, being the group with stable mosaicism the largest one. Collected evidence supports the marked similarities among patients carrying somatic or germline NLRP3 variants. The overrepresentation of NLRP3 mosaicism in late-onset forms should be considered in patients with inflammatory manifestations starting in adulthood. Analysis of mosaicism at the biological level confirms the two known patterns of corporal distribution and reveals that mosaicism remains stable over time in most patients, but it may also vary during the course of the disease.

Humans↗
PubMed1992

Clonal evolution in primary 5q-syndrome.

Primary 5q-syndrome is a type of myelodysplastic syndrome characterized by refractory anemia, thrombocytosis, and hypolobulated megakaryocytes. The risk of leukemic transformation is low. A case of 5q- syndrome that occurred in a 42-year-old woman and was complicated by leukemic transformation 7 years after the initial diagnosis is reported. An additional clonal karyotypic anomaly, del(7q), was seen in the leukemic cells. The literature on leukemic and karyotypic evolution of primary 5q- syndrome is reviewed and the implication of karyotypic evolution is discussed.

Acute Disease↗
PubMed1979

Clonal evolution of myeloma cells leads to quantitative changes in immunoglobulin secretion and surface antigen expression.

We report that a cloned population of tumor cells can rapidly produce variants that differ in their quantitative expression of surface proteins and in their rate of immunoglobulin secretion. A fresh clonal isolate of S107 myeloma cells possessing large amounts of surface IgA was continuously passaged in vitro for 2 years. During this period, fluorescence-activated cell sorter analysis indicated the development of subpopulations possessing decreased amounts of surface IgA. Cells from these variant subpopulations were isolated by first using the cell sorter to enrich for cells with decreased amounts of surface IgA and then cloning the selected population in soft agar. The 50 sublines that were isolated showed heritable differences in their levels of surface IgA and H-2 antigens and in their rates of myeloma protein secretion. Sublines having either large amounts, intermediate amounts, or absence of surface IgA also had corresponding large amounts, intermediate amounts, or absence of myeloma protein secretion. In contrast, a decrease or loss of surface Ig did not correlate with a decrease or loss of viral envelope glycoprotein gp71 and H-2 antigens. The variants did not resemble the phenotypes of less-differentiated normal lymphocyte populations of the B-cell lineage. The isolation and characterization of these variants allows us to explore the mechanisms and pathways of tumor cell differentiation as well as to study the regulation and function of cell surface proteins.

Animals↗
PubMed1985

Translocation 2;11 and other significant chromosome changes in acute monoblastic leukemia (M5) with clonal evolution: sequential clinical and cytogenetic studies.

An elderly woman presented with pancytopenia resulting from acute monoblastic leukemia (AMoL) type M5a. At the time of diagnosis, the marrow metaphase studies revealed a pseudodiploid idiogram: 46,XX,t(2;11)(q37;q23),(t(7;9;10)(q22;q22;p13). At relapse, 7 months later, a clonal derivative of the initial pseudodiploid pattern was identified. Though alterations of chromosome regions 7q22 and 9q22 are frequently seen in acute nonlymphocytic leukemia (ANLL), 11q structural anomalies are even more specific for this group of leukemias, and the involvement of band 11q23 is particularly striking in AMoL. Various chromosomes may take part in translocations with chromosome #11, but the participation of chromosome #2 as in this case is apparently rare.

Aged↗
PubMed1986

Borderline malignant serous tumors of the ovary maintained on extracellular matrix: evidence for clonal evolution and invasive potential.

Four cases of advanced stage (II or III) and one case of early stage (IC) borderline malignant serous cystadenocarcinomas of the ovary were maintained on culture dishes coated with an extracellular matrix (ECM) produced by bovine corneal endothelial cells. Cells harvested for chromosomal analysis after 2-3 days showed diploid or near-diploid modalities in all cases. Banded chromosome studies in two cases revealed nonrandom clonal abnormalities with trisomy 2, 7, and 12 in seven of 13 metaphases. No structural abnormalities were noted. These cytogenetic findings differ from those found in malignant serous tumors of the ovary. In addition, borderline tumor cells digested the ECM in all cases and formed a cribiform pattern within a few days of primary culture. This study suggests clonal progression from early to advanced stages of borderline malignant serous tumors; readily distinguishable from overtly malignant serous tumors of the ovary. Ability of tumor cells derived from both primary tumors and metastatic implants to digest the ECM implies the possibility that borderline serous tumors have invasive potential.

Adult↗
PubMed1992

Clonal evolution in a myeloid cell line transformed to interleukin-3 independent growth by retroviral transduction and expression of p210bcr/abl.

Current evidence suggests that the expression of the tyrosine kinase p210bcr/abl in chronic myelogenous leukemia (CML) may directly induce the initial phase of granulocytic hyperplasia. However, the dysregulation of additional genes appears to be required for transition to the acute leukemic phase, as inferred by the appearance of recurrent secondary cytogenetic abnormalities in the majority of patients. To determine whether the expression of p210bcr/abl alone is responsible for this genetic instability, we introduced and expressed the bcr/abl gene from a retroviral vector in a clone of the interleukin-3 (IL-3) dependent myeloblastic 32D C13(G) cell line. Clonal and polyclonal cells transformed to IL-3 independent growth were observed for a period extending up to 6 months for changes in the expression of p210bcr/abl, cell proliferation, inhibition by prostaglandin E1 (PGE1), forskolin, and cyclic adenosine monophosphate (cAMP) analogues, regulation of the cell cycle, and karyotype. Whereas the properties of control vector infected 32D C13(G)' cells remained stable over time, cells expressing p210bcr/abl were phenotypically unstable. In cells expressing p210bcr/abl, we observed selective modulation of p210bcr/abl mRNA and protein expression, evolution from partial to full abrogation of IL-3 dependence, reduced serum requirements, increased cell proliferation, decreased inhibition by PGE1 and cAMP analogues, and the appearance of new structural and numerical chromosomal abnormalities with successive cell passages. These results indicate that expression of p210bcr/abl can directly predispose 32D C13(G)' cells to genetic instability, promotes the emergence of clones with an increased proliferative advantage, and may represent an in vitro model suitable for the study of mechanisms underlying progression to the acute leukemic phase in CML.

Aneuploidy↗
PubMed1987

Clonal evolution of t(14;18) follicular lymphomas demonstrated by immunoglobulin genes and the 18q21 major breakpoint region.

A 2.8-kilobase major breakpoint region on chromosome segment 18q21 is the site of most t(14;18) translocations typical of human follicular lymphomas. Breaks are focused at the 5' end of joining (JH) regions of immunoglobulin (Ig) on chromosome 14, indicating that the translocation occurs at a pre-B-cell stage during attempted heavy (H) chain joining. A new gene from 18q21 (Bcl-2) is placed in the H chain locus creating a unique, translocation-specific JH;18q21 rearrangement that presumably represents a transformation event. In addition, normal Ig gene joining occurs in a H before light (L) chain and K before lambda cascade, creating ordered clonal markers. These serial markers were examined to determine if variations in Ig gene patterns during the natural history of lymphomas represent the emergence of truly separate neoplasms or heterogeneity of a single neoplasm. We examined 45 serial biopsies from 16 B follicular lymphoma patients; six cases showed variation in Ig gene patterns over time. Seven individuals had a detectable JH;18q21 rearrangement present, and it remained unchanged over 5-10 years. Further rearrangements of H chain genes occurred on the normal chromosome 14 within evolving subclones of the original tumor. Lambda L chains also underwent additional rearrangements in two instances, while K gene patterns remained unchanged. All variations in the normal H and L chain genes were 2 degrees rearrangements occurring at a mature B-cell stage following the initial successful rearrangement of a H and L chain. In contrast the t(14;18) breakpoint was conserved in each individual, indicating that evolving neoplastic subpopulations arose from a common clonal progenitor cell.

Alleles↗
PubMed1986

Clonal evolution of T-cell chronic lymphocytic leukaemia in a patient with ataxia telangiectasia.

Ataxia telangiectasia (A-T) is an autosomal recessive disorder in which patients show an unusual predisposition to malignant disease, including T-cell chronic lymphocytic leukaemia. We report here the steady growth over 5 years of a complex, cytogenetically abnormal clone of T lymphocytes in an A-T patient who was subsequently found to have an OKT3/OKT8 chronic lymphocytic leukaemia. The tumour cells at diagnosis had clearly evolved from a pre-existing, cytogenetically abnormal T-cell clone which contained an inv(14) chromosomal inversion alone.

Ataxia Telangiectasia↗
PubMed1987

Mast cell disease followed by leukemia with clonal evolution.

A 29-yr old woman developed urticaria pigmentosa which subsequently progressed through systemic mastocytosis to Philadelphia chromosome negative (Ph neg) chronic myelogenous leukemia (CML) with t(8;17). Further cytogenetic evolution occurred at the time of transformation to the aggressive phase of the disease. Unlike Ph-positive CML, chromosome number 9 was not involved, nor was the breakpoint cluster region located at band 22q11. This clearly separates this case from other Ph-negative CML patients who do have involvement of 9q34 or the breakpoint cluster region. Since this is the first case of its type to be reported with cytogenetic abnormalities, the clinical relevance of the unique chromosomal rearrangement t(8;17)(p11;q25) in the setting of systemic mastocytosis is unclear. Additional cases need to be reported to determine if this genetic rearrangement is a nonrandom marker of leukemia evolving in a setting of malignant mast cell disease.

Adult↗
PubMed1990

Analysis of inferred cytogenetic clonal evolution in a metastatic human ovarian carcinoma.

Cytogenetic analyses of solid tumors are hampered both by the difficulties in preparing high-quality banded metaphases and the high degree of karyotypic heterogeneity. Three specimens were obtained from a single patient with serous carcinoma for karyotyping and compared to determine whether the tumor was multifocal or metastatic. All three specimens were hypodiploid, sharing marker chromosomes, thus indicating metastasis. To simplify comparison between the specimens, a diagram of the inferred cytogenetic evolution of the cells analysed was developed. This method afforded a simple means of comparing the different tumor sites in a single patient and might also be applied to sequential samples from patients.

Chromosome Aberrations↗