Chromosome 3q21 abnormalities associated with hyperactive thrombopoiesis in acute blastic transformation of chronic myeloid leukemia

Two patients with acute blastic transformation of chronic myeloid leukemia (CML) associated with strikingly elevated platelet counts showed abnormalities of chromosome 3q in addition to the standard Philadelphia (Ph1) chromosome translocation. The first patient had an inversion of chromosome 3 (q21q26) cytologically identical to an inversion 3 previously reported in de novo acute megakaryoblastic leukemia, and the second patient showed a translocation between chromosome 3q and the chromosome 9 homologue not involved in the Ph1 translocation, [t(3;9)(q21;q34)]. Previous studies had incriminated either 3q21 or 3q26 as the locus for a regulatory thrombopoietic gene, but the current study suggests that 3q21 is the relevant site.

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Chromosome 3q21 abnormalities associated with hyperactive thrombopoiesis in acute blastic transformation of chronic myeloid leukemia

Blood ◽

10.1182/blood.v68.3.652.652 ◽

1986 ◽

Vol 68 (3) ◽

pp. 652-657 ◽

Cited By ~ 67

Author(s):

R Bernstein ◽

A Bagg ◽

M Pinto ◽

D Lewis ◽

B Mendelow

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Chromosome Translocation ◽

Chromosome 9 ◽

Chromosome 3 ◽

Acute Megakaryoblastic Leukemia ◽

Blastic Transformation ◽

Megakaryoblastic Leukemia ◽

Platelet Counts

Abstract Two patients with acute blastic transformation of chronic myeloid leukemia (CML) associated with strikingly elevated platelet counts showed abnormalities of chromosome 3q in addition to the standard Philadelphia (Ph1) chromosome translocation. The first patient had an inversion of chromosome 3 (q21q26) cytologically identical to an inversion 3 previously reported in de novo acute megakaryoblastic leukemia, and the second patient showed a translocation between chromosome 3q and the chromosome 9 homologue not involved in the Ph1 translocation, [t(3;9)(q21;q34)]. Previous studies had incriminated either 3q21 or 3q26 as the locus for a regulatory thrombopoietic gene, but the current study suggests that 3q21 is the relevant site.

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Monoclonal antiglycophorin as a probe for erythroleukemias

Blood ◽

10.1182/blood.v61.4.645.bloodjournal614645 ◽

1983 ◽

Vol 61 (4) ◽

pp. 645-651 ◽

Cited By ~ 2

Author(s):

MF Greaves ◽

C Sieff ◽

PA Edwards

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Blast Crisis ◽

Significant Proportion ◽

Erythroid Cell ◽

Glycophorin A ◽

Acute Megakaryoblastic Leukemia ◽

Megakaryoblastic Leukemia

A monoclonal antibody (LICR.LON.R10) specific for the major sialoglycoprotein of the erythroid cell membrane, glycophorin A (alpha), has been used to test the possibility that “cryptic” erythroleukemia may be diagnosed as acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). In addition to 27 overt erythroleukemias, 724 leukemias, including 329 ALL (103 in relapse), 205 AML, and 109 blast crises of Ph1-positive chronic myeloid leukemia, were analyzed. Twenty cases with a significant proportion of glycophorin-A-positive (gA+) cells were found; 8 of these (5 AML and 3 blast crises of chronic myeloid leukemia, CML) had an obvious erythroid component, but 12 others were diagnosed as AML (2), AMML (1), CML in myeloid blast crisis (4) or megakaryoblastic blast crisis (1), acute megakaryoblastic leukemia (2), or acute lymphoblastic leukemia (2). The latter two patients had no immunologic evidence supporting a diagnosis of ALL and were resistant to chemotherapy. We conclude that AML and ALL only very rarely express gA, and these are probably genuine “cryptic” erythroleukemias. Other gA+ leukemias (megakaryoblastic and CML blast crises) may arise from bi- or pluripotent stem cells and contain distinct and separable blast cell populations.

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Monoclonal antiglycophorin as a probe for erythroleukemias

Blood ◽

10.1182/blood.v61.4.645.645 ◽

1983 ◽

Vol 61 (4) ◽

pp. 645-651 ◽

Cited By ~ 69

Author(s):

MF Greaves ◽

C Sieff ◽

PA Edwards

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Blast Crisis ◽

Significant Proportion ◽

Erythroid Cell ◽

Glycophorin A ◽

Acute Megakaryoblastic Leukemia ◽

Megakaryoblastic Leukemia

Abstract A monoclonal antibody (LICR.LON.R10) specific for the major sialoglycoprotein of the erythroid cell membrane, glycophorin A (alpha), has been used to test the possibility that “cryptic” erythroleukemia may be diagnosed as acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). In addition to 27 overt erythroleukemias, 724 leukemias, including 329 ALL (103 in relapse), 205 AML, and 109 blast crises of Ph1-positive chronic myeloid leukemia, were analyzed. Twenty cases with a significant proportion of glycophorin-A-positive (gA+) cells were found; 8 of these (5 AML and 3 blast crises of chronic myeloid leukemia, CML) had an obvious erythroid component, but 12 others were diagnosed as AML (2), AMML (1), CML in myeloid blast crisis (4) or megakaryoblastic blast crisis (1), acute megakaryoblastic leukemia (2), or acute lymphoblastic leukemia (2). The latter two patients had no immunologic evidence supporting a diagnosis of ALL and were resistant to chemotherapy. We conclude that AML and ALL only very rarely express gA, and these are probably genuine “cryptic” erythroleukemias. Other gA+ leukemias (megakaryoblastic and CML blast crises) may arise from bi- or pluripotent stem cells and contain distinct and separable blast cell populations.

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THE CASE VARIANT TRANSLOCATION T(3;9;22)(P24;Q34;Q11) IN CHRONIC MYELOID LEUKEMIA

Problems in oncology ◽

10.37469/0507-3758-2018-64-6-810-814 ◽

2018 ◽

Vol 64 (6) ◽

pp. 810-814

Author(s):

Kodirzhon Boboev ◽

Yuliana Assesorova ◽

Kh. Karimov ◽

B. Allanazarova

Keyword(s):

Adverse Effect ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Fusion Gene ◽

Genetic Locus ◽

Philadelphia Chromosome ◽

Chromosome 9 ◽

Banding Technique ◽

Variant Translocation

This paper presents a case of chronic myeloid leukemia with an earlier unknown variant translocation t (3; 9; 22) (p24; q34; q11) detected by cytogenetic research using the GTG-banding technique. Despite the absence of the classical Philadelphia chromosome, the presence of chromosome 9 and 22 derivatives, as well as the BCR-ABL fusion gene, allow this translocation to be considered pathogenetic for CML. A good response of the patient to the treatment with glivec is that there is no adverse effect on the pathogenesis of the disease of an additional genetic locus (3p24) involved in complex restructuring.

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Efficacy of combining dasatinib and FLAG-IDA for patients with chronic myeloid leukemia in blastic transformation

Haematologica ◽

10.3324/haematol.2011.057513 ◽

2011 ◽

Vol 97 (3) ◽

pp. 473-474 ◽

Cited By ~ 22

Author(s):

D. Milojkovic ◽

A. Ibrahim ◽

A. Reid ◽

L. Foroni ◽

J. Apperley ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Blastic Transformation

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DNA Damage and DNA Damage Response in Chronic Myeloid Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms21041177 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1177 ◽

Cited By ~ 2

Author(s):

Popp ◽

Kohl ◽

Naumann ◽

Flach ◽

Brendel ◽

...

Keyword(s):

Dna Damage ◽

Chronic Myeloid Leukemia ◽

Dna Damage Response ◽

Myeloid Leukemia ◽

Molecular Response ◽

Blastic Transformation ◽

Γh2ax Foci ◽

Damage Response ◽

Nhej Repair ◽

Repair Mechanisms

DNA damage and alterations in the DNA damage response (DDR) are critical sources of genetic instability that might be involved in BCR-ABL1 kinase-mediated blastic transformation of chronic myeloid leukemia (CML). Here, increased DNA damage is detected by γH2AX foci analysis in peripheral blood mononuclear cells (PBMCs) of de novo untreated chronic phase (CP)-CML patients (n = 5; 2.5 γH2AX foci per PBMC ± 0.5) and blast phase (BP)-CML patients (n = 3; 4.4 γH2AX foci per PBMC ± 0.7) as well as CP-CML patients with loss of major molecular response (MMR) (n = 5; 1.8 γH2AX foci per PBMC ± 0.4) when compared to DNA damage in PBMC of healthy donors (n = 8; 1.0 γH2AX foci per PBMC ± 0.1) and CP-CML patients in deep molecular response or MMR (n = 26; 1.0 γH2AX foci per PBMC ± 0.1). Progressive activation of erroneous non-homologous end joining (NHEJ) repair mechanisms during blastic transformation in CML is indicated by abundant co-localization of γH2AX/53BP1 foci, while a decline of the DDR is suggested by defective expression of (p-)ATM and (p-)CHK2. In summary, our data provide evidence for the accumulation of DNA damage in the course of CML and suggest ongoing DNA damage, erroneous NHEJ repair mechanisms, and alterations in the DDR as critical mediators of blastic transformation in CML.

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Clinical significance of dasatinib-induced pleural effusion in patients with de novo chronic myeloid leukemia

Hematology Reports ◽

10.4081/hr.2018.7474 ◽

2018 ◽

Vol 10 (3) ◽

Cited By ~ 1

Author(s):

Aya Nakaya ◽

Shinya Fujita ◽

Atsushi Satake ◽

Takahisa Nakanishi ◽

Yoshiko Azuma ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Clinical Features ◽

Myeloid Leukemia ◽

De Novo ◽

Late Onset ◽

Molecular Response ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Treatment Agent

Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PEpositive patients was higher than that of PEnegative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.

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Accumulation of DNA Damage and Alteration of the DNA Damage Response in Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2019-122698 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5364-5364

Author(s):

Henning D. Popp ◽

Vanessa Kohl ◽

Johanna Flach ◽

Susanne Brendel ◽

Helga Kleiner ◽

...

Keyword(s):

Dna Damage ◽

Myeloid Leukemia ◽

Research Funding ◽

De Novo ◽

Chronic Phase ◽

Molecular Response ◽

Healthy Individuals ◽

Blastic Transformation ◽

Γh2ax Foci ◽

Tki Treatment

The accumulation of DNA damage and the alteration of the DNA damage response (DDR) are critical features of genetic instability that is presumed to be implicated in BCR/ABL1-mediated blastic transformation of chronic myeloid leukemia (CML). The aim of our study was to analyze underlying mechanisms of genetic instability with regard to DNA damage such as DNA double-strand breaks (DSB), DSB repair and DDR signaling during blastic transformation of CML. Immunofluorescence microscopy of γH2AX was performed for quantification of DSB in peripheral blood mononuclear cells (PBMC) of 8 healthy individuals, 24 chronic phase (CP)-CML patients under current/discontinued tyrosine kinase inhibitor (TKI) treatment (21 patients in deep molecular response (DMR), 3 patients in major molecular response (MMR)), 5 CP-CML patients under current/discontinued TKI treatment with loss of MMR, 3 de novo non-treated CP-CML patients and 2 blast phase (BP)-CML patients. In addition, immunofluorescence microscopy of γH2AX/53BP1 was used for semi-quantification of error-prone DSB repair. Furthermore, immunoblotting of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53 was performed in PBMC of CML patients in comparison to PBMC of healthy individuals. Our analysis revealed an increase in numbers of γH2AX foci in PBMC of CP-CML patients under current/discontinued TKI treatment with loss of MMR (1.8 γH2AX foci per PBMC ± 0.4), in PBMC of de novo non-treated CP-CML patients (2.3 γH2AX foci per PBMC ± 0.7) and in PBMC of BP-CML patients (4.9 γH2AX foci per PBMC ± 0.9) as compared to the number of γH2AX foci in PBMC of healthy individuals (1.0 γH2AX foci per PBMC ± 0.1) and in PBMC of CP-CML patients under current/discontinued TKI treatment in DMR/MMR (1.0 γH2AX foci per PBMC ± 0.1) (Figure 1A and B). Analysis of co-localizing γH2AX/53BP1 foci in PBMC suggested progressive activation of error-prone nonhomologous end-joining repair mechanisms during blastic transformation in CML. Signatures of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53 indicated alterations of the DDR. In summary, our data provide evidence for an accumulation of DNA damage in PBMC of CML patients towards BP-CML patients. We hypothesize that ongoing DSB generation, error-prone DSB repair and DDR alterations might be critical mechanisms of blastic transformation in CML. Figure 1 Analysis of γH2AX foci in freshly isolated peripheral blood mononuclear cells (PBMC) of healthy individuals and chronic myeloid leukemia (CML) patients. (A) Exemplary immunofluorescence microscopic images of γH2AX foci (green, Alexa 488) and cell nuclei (blue, DAPI) in PBMC of a healthy individual (HEALTHY#3), a chronic phase CML patient with a deep molecular response to tyrosine kinase inhibitor (CP-CML DMR#16), a de novo non-treated chronic phase CML patient (CP-CML#1) and a blast phase CML patient (BP-CML#2). (B) γH2AX foci levels in PBMC of healthy individuals and in PBMC of CML patients. Figure 1 Disclosures Saussele: Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Fabarius:Novartis: Research Funding.

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