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Acute myelogenous leukemia and thrombocythemia associated with an abnormality of chromosome No. 3
Acute Myelogenous Leukemia and Thrombocythemia Associated with an Abnormality of Chromosome No. 3 Donald L. Sweet, Harvey M. Golomb, Janet D. Rowley, and James M. Vardiman
ABSTRACT:
The association of thrombocythemia with acute myelogenous leukemia (AML) is unusual.
A patient with markedly increased platelet counts in association with abnormal megakaryocytes was diagnosed as having AML. In addition a karyotypic abnormality involving a translocation of the long arm of a No. 3 chromosome was identified by Q.banding techniques. The translocat/on involved the other chromosome No. 3 [ins (3;3) (q26;q21q26)]. A specific structural rearrangement in human chromosomes in AML may be associated with abnormal megakaryocytes and increased platelets.
INTRODUCTION The nonrandom nature of chromosomal abnormalities in adult acute nonlymphocytic leukemia (ANLL) has recently been reported by Rowley and Potter [1]. There have been a number of reports correlating specific chromosomal abnormalities, identified by means of banding techniques, with particular clinical observations. We have reported the association of a 15;17 translocation which appears to be a common abnormality in patients with acute promyelocytic leukemia (APL) [2 -4]. The 8;21 translocation [5] observed in 5 to 10% of patients with ANLL is thought to be associated with a less malignant clinical course than other abnormalities [8]. We recently studied a patient with acute myelogenous leukemia {AML} who presented with thrombocythemia, an unusual association. This patient's megakaryocytes were of abnormal morphology. In addition, a persistent karyotypic abnormality involving a translocation of the long arm of chromosome No. 3 [ins(3;3) Cq26;q21q26)] was identified by Q-banding techniques [1]. This is the second such patient we have identified with this association, which suggests a region on the long arm of chromosome No. 3 is concerned with the regulation of megakaryocyte proliferation.
From the Departmentsof Medicine and Pathology,The Universityof Chicago,and the FranklinMcLean MemorialResearchInstitute (operated byThe Universityof Chicagofor the U.S. DepartmentofEnergyunder ContractNo. EY-76-C-02-0069},Chicago,Illinois. Address reprint requests to: Donald L. Sweet, M.D., Box 420, 950 East 59th Street, Chicago, IL 60637.
Received/anuary 8, 1979; accepted March 9, 1979.
© Elsevier North Holland, Inc., 1979 Cancer Genetics and Cytogenetics1, 33-37 (1979) 0165-4608/79/01003305502.25
34
D.L. Sweet eta|.
SUBJECT AND METHODS Case Report A 46-year old white female sought medical attention because of fatigue and progressive dyspnea on exertion over a 3-week period. Her history revealed treatment for stage II cervical carcinoma 6-1/2 years previously, including the 3-day course of an indwelling radiation source followed by 36 days of external radiotherapy to a pelvic port. Bilateral flame-shaped retinal hemorrhages were the only abnormality found on physical examination. Laboratory tests revealed a hematocrit of 39% (after the administration of 4 units of packed red blood cells at her community hospital), white blood cell (WBC) count of 165,000/mm 3 with 90% blast forms, and a platelet count of 1,731,000/mm 3 (Fig. 1). An occasional megakaryocyte fragment was seen. Bone marrow aspiration showed 83.5% blasts which morphologically and cytochemically were diagnostic of acute myelogenous leukemia. There were 38 megakaryocytes per 50 OPF.* More than two-thirds of the megakaryocytes were small with monolobed or bilobed nuclei and with mature-appearing, grey, granular cytoplasm (Fig. 1). Treatment consisted of two 5-day cycles of cytosine arabinoside (AraC) and 6thioguanine, which did not affect the WBC. Three courses of AraC and Daunomycin Figure 1 Peripheral blood smear shows numerous blasts and thrombocytes (a). Binucleate micromegakaryocytes (arrows) were the prominent type of megakaryocytes present in the bone marrow aspirate (b). Wright-1 Giemsa × 1000.
(a)
(b)
*Normal megakaryocytecounts in the bone marrow are given as 0.1-3.8 per 50 Oil-Power Fields (OPF) [7].
35
Thrombocythemia and Chromosome 3 Abnormality
were subsequently administered. Although peripheral leukopenia and thrombocytopenia occurred, no evidence of a bone marrow response was observed. Combination therapy with cyclophosphamide, vincristine, AraC, and prednisone was initiated, but again no response was obtained after three courses, and the patient expired. Autopsy permission was denied.
Chromosome Analysis The chromosomal analysis was performed initially on standard Giemsa-stained slides without cover slips, as previously described [1]. For fluorescence analysis, the slides were destained with either 95% methanol or 1:3 acetic acid:methanol fixative; they were then stained with quinacrine mustard, pH 5.5, for 2 0 - 6 0 rain, rinsed twice in McIlvain's buffer, pH 5.5, and mounted in buffer. The cells which had previously been photographed with Giemsa stain were now examined with the Leitz fluorescence microscope with epi-illumination and were photographed with Panatomic X film. Karyotype analysis of the cells was performed with the use of both photographs of each cell. The chromosomes were identified according to the Paris Conference [8], and the karyotypes were expressed as recommended under this system. RESULTS The peripheral blood myeloblasts were distinctly different morphologically from the bilobed megakaryocytes seen in the bone marrow (Fig. 1). The karyotype of our patient was 45,XX,ins(3;3)(q26;q21q26),-7 (Fig. 2). Four samples were obtained while Figtwe 2 Partial karyotypes of two cells show chromosome pair No. 3. (a) Chromosomes stained with quinacrine mustard were photographed with ultraviolet light. (b} The same chromosomes were stained with standard Giemsa stain. (Top pairs) Bone marrow cell from this patient. The long arm of the first No. 3 is longer than normal due to an insertion of the distal portion of the long arm of the second No. 3, which is too short [ins(3;3) (q26;q21q26)]. (Bottom pairs) Peripheral blood lymphocyte showing the normal appearance of both No. 3's.
(a)
(b)
36
D.L. Sweet et al. the patient was unresponsive to therapy. Three samples revealed the abnormality; one sample had no analyzable metaphases. A total of 27 cells were examined with fluorescence; 19 had the abnormality. Cells with a normal karyotype were observed in a 72-hr culture of peripheral blood lymphocytes and thus established the abnormality as an acquired one.
DISCUSSION
Thrombocythemia is an elevated platelet count (> 600,000/ram 3) due to a primary myeloproliferative disorder, whereas thrombocytosis usually refers to a self-limited reactive platelet elevation. Thrombocythemia in patients with acute leukemia is a rare occurrence. It is frequently associated with other myeloproliferative disorders, such as essential thrombocythemia, polycythemia vera, and chronic granulocytic leukemia, as well as lymphomas [9]. The patient reported on here, as well as a patient reported on elsewhere [1,12], had breaks involving bands 3q25 or 26 and in 3q21. The first patient had a platelet count of 600,000/ram :3 [12]. A missing chromosome 7 was not seen in the first patient and probably has no association with the platelet count in this patient. These are the only patients in our series that demonstrate chromosome breaks in this region, and they are the only patients with platelet counts above 600,000 out of a consecutive series of 108 patients with ANLL. A third patient with acute myelomonocytic leukemia presented with a platelet count of 240,000 and a 46,XY,t(3;5)(q25;q337) karyotype [12]. We have seen two patients with translocations resulting from breaks in the short arm of No. 3; neither of these patients had thrombocythemia [13,14]. We have studied a patient with a hypereosinophilic syndrome who demonstrated a t(3;5)(p21;q13) abnormality but a normal platelet count [13]. A patient with chronic granulocytic leukemia, developed a 3p;llq translocation in blast crisis [14], and two of our ANLL patients were lacking a No. 3 altogether [1]. Chromosome No. 3 thus is frequently involved in chromosomal changes in hematologic disorders. Philip recently reported on three patients, each of whose marrow cells showed a break in band 3q27 and a translocation with either No. I or No. 5 [15,16]. Two of these patients had multiple myeloma and one had erythroleukemia; in each, multiple chromosomal rearrangements were present. Platelet counts were not reported. One patient with juvenile "chronic granulocytic" leukemia has been reported with a translocation between 3q and 7q; the break in No. 3 was near band q26146,XX,t(3; 7)(q26;q11)] [17]. This patient had a platelet count of 33,000/mm 3 and a paucity of megakaryocytes in his bone marrow. The association in our two patients of a rare clinical finding, marked thrombocythemia in acute leukemia, with a structural rearrangement involving the same region of chromosome No. 3, raises the question of whether these two observations are causally related. Present evidence indicates that abnormalities of the short arm of No. 3 are not associated with thrombocythemia, and that patients with essential thrombocythemia have normal No. 3's. It is possible that the involved band on No. 3 contains the locus that controls megakaryocytic proliferation and platelet production. Alternatively, it may be that these translocations, which bring chromosomal material together in unusual combinations, produce either genetic activation or inactivation of one or both of the adjacent genes. Since the genetic constitution of these chromosomes is still unknown, we cannot evaluate either of these possibilities at present. The presence of nonrandom structural rearrangements, such as the 8;21 translocation in ANLL, the 15;17 translocation in APL, and the 9;22 translocation in CML, provides material for the study of the chromosomal location of genes concerned with the regulation of proliferation and maturation of bone marrow elements.
Thrombocythemia and Chromosome 3 Abnormality
37
This research was supported by the Leukemia Research Foundation, The Thomas Moore Fund, The National Foundation-March of Dimes, and an Otho S.A. Sprague Memorial Institutional Grant. Dr. Sweet is a Junior Faculty Clinical Fellow of the American Cancer Society.
REFERENCES
1. Rowley JD, Potter D: (1976): Chromosomal banding patterns in acute leukemia. Blood 47, 705-722. 2. Golomb HM, Rowley J, Vardiman J, Baron J, Locker G, Krasnow S (1978): Partial deletion of the long arm of chromosome 17; a specific abnormality in acute promyelocytic leukemia? Arch Intern Med 136, 825 -828. 3. Rowley JD, Golomb HM, Vardiman J, Fukuhara S, Dougherty C, Potter D (1977): Further evidence for a non-random chromosomal abnormality in acute promyelocytic leukemia. Int J Cancer 20, 869 - 872. 4. Testa JR, Golomb HM, Rowley JD, Vardiman JW, Sweet DL (1978)-Hypergranular promyelocytic leukemia (APL): cytogenetic and ultrastructural specificity. Blood 52, 272 - 280. 5. Rowley JD (1973): Identification of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet 16, 109 - 112. 6. Sakurai M, Sandberg AA (1975): Chromosomes and causation of human cancer and leukemia. XI. Correlations of karyotypes with clinical features of acute myeloblastic leukemia. Cancer 37, 285-299. 7. Williams WJ (1972): Examination of the bone marrow. In: Hematology, WJ Williams, E Beutier, AJ Erslev, and EW Rundles, eds. McGraw-Hill, New York, p. 26. 8. Paris Conference (1971): Standardization in human cytogenetics. Birth Defects: Original Article Series, Vol 7, No 7, The National Foundation, New York, 1972. 9. Williams WJ (1972): Thrombocytosis. In: Hematology, WJ Williams, E Beutler, AJ Erslev, and RW Rundles, eds. McGraw-Hill, New York, pp. 1162 - 1185. 10. Trujillo J, Cork A, Hart JS, George SL, Freireich EJ (1974): Clinical implications of aneuploid cytogenetic profiles in adult acute leukemia. Cancer 33,824- 834. 11. Sakurai M, Sandberg AA (1974): Chromosomes and causation of human cancer and leukemia. IX. Prognostic and therapeutic value of chromosomal findings in acute myeloblastic leukemia. Cancer 33, 1548 - 1557. 12. Golomb HM, Vardiman J, Rowley JD (1976): Acute nonlymphocytic leukemia in adults: correlations with Q-banded chromosomes. Blood 48, 9 - 21. 13. Bitran JD, Rowley JD, Plapp F, Golomb HM, Ultmann JE (1977): Chromosomal aneuploidy in a patient with hypereosinophilic syndrome: evidence for a malignant disease. Am J Med 63, 1010-1014. 14. Rowley ]D: unpublished observations. 15. Philip P (1975): A vulnerable point on human chromosome 3 in myeloproliferative disorders? Hereditas 81,124 - 125. 16. Philip P, Drivsholm A (1976): G-banding analysis of complex aneuploidy in multiple myeloma bone marrow cells. Blood 47, 6 9 - 77. 17. Altman AJ, Palmer CG, Baehner RL (1974): Juvenile "chronic granulocytic" leukemia: a panmyelopathy with prominent monocylic involvement and circulating monocyte colonyforming cells. Blood 43, 341 - 350.
ABSTRACT:
The association of thrombocythemia with acute myelogenous leukemia (AML) is unusual.
A patient with markedly increased platelet counts in association with abnormal megakaryocytes was diagnosed as having AML. In addition a karyotypic abnormality involving a translocation of the long arm of a No. 3 chromosome was identified by Q.banding techniques. The translocat/on involved the other chromosome No. 3 [ins (3;3) (q26;q21q26)]. A specific structural rearrangement in human chromosomes in AML may be associated with abnormal megakaryocytes and increased platelets.
INTRODUCTION The nonrandom nature of chromosomal abnormalities in adult acute nonlymphocytic leukemia (ANLL) has recently been reported by Rowley and Potter [1]. There have been a number of reports correlating specific chromosomal abnormalities, identified by means of banding techniques, with particular clinical observations. We have reported the association of a 15;17 translocation which appears to be a common abnormality in patients with acute promyelocytic leukemia (APL) [2 -4]. The 8;21 translocation [5] observed in 5 to 10% of patients with ANLL is thought to be associated with a less malignant clinical course than other abnormalities [8]. We recently studied a patient with acute myelogenous leukemia {AML} who presented with thrombocythemia, an unusual association. This patient's megakaryocytes were of abnormal morphology. In addition, a persistent karyotypic abnormality involving a translocation of the long arm of chromosome No. 3 [ins(3;3) Cq26;q21q26)] was identified by Q-banding techniques [1]. This is the second such patient we have identified with this association, which suggests a region on the long arm of chromosome No. 3 is concerned with the regulation of megakaryocyte proliferation.
From the Departmentsof Medicine and Pathology,The Universityof Chicago,and the FranklinMcLean MemorialResearchInstitute (operated byThe Universityof Chicagofor the U.S. DepartmentofEnergyunder ContractNo. EY-76-C-02-0069},Chicago,Illinois. Address reprint requests to: Donald L. Sweet, M.D., Box 420, 950 East 59th Street, Chicago, IL 60637.
Received/anuary 8, 1979; accepted March 9, 1979.
© Elsevier North Holland, Inc., 1979 Cancer Genetics and Cytogenetics1, 33-37 (1979) 0165-4608/79/01003305502.25
34
D.L. Sweet eta|.
SUBJECT AND METHODS Case Report A 46-year old white female sought medical attention because of fatigue and progressive dyspnea on exertion over a 3-week period. Her history revealed treatment for stage II cervical carcinoma 6-1/2 years previously, including the 3-day course of an indwelling radiation source followed by 36 days of external radiotherapy to a pelvic port. Bilateral flame-shaped retinal hemorrhages were the only abnormality found on physical examination. Laboratory tests revealed a hematocrit of 39% (after the administration of 4 units of packed red blood cells at her community hospital), white blood cell (WBC) count of 165,000/mm 3 with 90% blast forms, and a platelet count of 1,731,000/mm 3 (Fig. 1). An occasional megakaryocyte fragment was seen. Bone marrow aspiration showed 83.5% blasts which morphologically and cytochemically were diagnostic of acute myelogenous leukemia. There were 38 megakaryocytes per 50 OPF.* More than two-thirds of the megakaryocytes were small with monolobed or bilobed nuclei and with mature-appearing, grey, granular cytoplasm (Fig. 1). Treatment consisted of two 5-day cycles of cytosine arabinoside (AraC) and 6thioguanine, which did not affect the WBC. Three courses of AraC and Daunomycin Figure 1 Peripheral blood smear shows numerous blasts and thrombocytes (a). Binucleate micromegakaryocytes (arrows) were the prominent type of megakaryocytes present in the bone marrow aspirate (b). Wright-1 Giemsa × 1000.
(a)
(b)
*Normal megakaryocytecounts in the bone marrow are given as 0.1-3.8 per 50 Oil-Power Fields (OPF) [7].
35
Thrombocythemia and Chromosome 3 Abnormality
were subsequently administered. Although peripheral leukopenia and thrombocytopenia occurred, no evidence of a bone marrow response was observed. Combination therapy with cyclophosphamide, vincristine, AraC, and prednisone was initiated, but again no response was obtained after three courses, and the patient expired. Autopsy permission was denied.
Chromosome Analysis The chromosomal analysis was performed initially on standard Giemsa-stained slides without cover slips, as previously described [1]. For fluorescence analysis, the slides were destained with either 95% methanol or 1:3 acetic acid:methanol fixative; they were then stained with quinacrine mustard, pH 5.5, for 2 0 - 6 0 rain, rinsed twice in McIlvain's buffer, pH 5.5, and mounted in buffer. The cells which had previously been photographed with Giemsa stain were now examined with the Leitz fluorescence microscope with epi-illumination and were photographed with Panatomic X film. Karyotype analysis of the cells was performed with the use of both photographs of each cell. The chromosomes were identified according to the Paris Conference [8], and the karyotypes were expressed as recommended under this system. RESULTS The peripheral blood myeloblasts were distinctly different morphologically from the bilobed megakaryocytes seen in the bone marrow (Fig. 1). The karyotype of our patient was 45,XX,ins(3;3)(q26;q21q26),-7 (Fig. 2). Four samples were obtained while Figtwe 2 Partial karyotypes of two cells show chromosome pair No. 3. (a) Chromosomes stained with quinacrine mustard were photographed with ultraviolet light. (b} The same chromosomes were stained with standard Giemsa stain. (Top pairs) Bone marrow cell from this patient. The long arm of the first No. 3 is longer than normal due to an insertion of the distal portion of the long arm of the second No. 3, which is too short [ins(3;3) (q26;q21q26)]. (Bottom pairs) Peripheral blood lymphocyte showing the normal appearance of both No. 3's.
(a)
(b)
36
D.L. Sweet et al. the patient was unresponsive to therapy. Three samples revealed the abnormality; one sample had no analyzable metaphases. A total of 27 cells were examined with fluorescence; 19 had the abnormality. Cells with a normal karyotype were observed in a 72-hr culture of peripheral blood lymphocytes and thus established the abnormality as an acquired one.
DISCUSSION
Thrombocythemia is an elevated platelet count (> 600,000/ram 3) due to a primary myeloproliferative disorder, whereas thrombocytosis usually refers to a self-limited reactive platelet elevation. Thrombocythemia in patients with acute leukemia is a rare occurrence. It is frequently associated with other myeloproliferative disorders, such as essential thrombocythemia, polycythemia vera, and chronic granulocytic leukemia, as well as lymphomas [9]. The patient reported on here, as well as a patient reported on elsewhere [1,12], had breaks involving bands 3q25 or 26 and in 3q21. The first patient had a platelet count of 600,000/ram :3 [12]. A missing chromosome 7 was not seen in the first patient and probably has no association with the platelet count in this patient. These are the only patients in our series that demonstrate chromosome breaks in this region, and they are the only patients with platelet counts above 600,000 out of a consecutive series of 108 patients with ANLL. A third patient with acute myelomonocytic leukemia presented with a platelet count of 240,000 and a 46,XY,t(3;5)(q25;q337) karyotype [12]. We have seen two patients with translocations resulting from breaks in the short arm of No. 3; neither of these patients had thrombocythemia [13,14]. We have studied a patient with a hypereosinophilic syndrome who demonstrated a t(3;5)(p21;q13) abnormality but a normal platelet count [13]. A patient with chronic granulocytic leukemia, developed a 3p;llq translocation in blast crisis [14], and two of our ANLL patients were lacking a No. 3 altogether [1]. Chromosome No. 3 thus is frequently involved in chromosomal changes in hematologic disorders. Philip recently reported on three patients, each of whose marrow cells showed a break in band 3q27 and a translocation with either No. I or No. 5 [15,16]. Two of these patients had multiple myeloma and one had erythroleukemia; in each, multiple chromosomal rearrangements were present. Platelet counts were not reported. One patient with juvenile "chronic granulocytic" leukemia has been reported with a translocation between 3q and 7q; the break in No. 3 was near band q26146,XX,t(3; 7)(q26;q11)] [17]. This patient had a platelet count of 33,000/mm 3 and a paucity of megakaryocytes in his bone marrow. The association in our two patients of a rare clinical finding, marked thrombocythemia in acute leukemia, with a structural rearrangement involving the same region of chromosome No. 3, raises the question of whether these two observations are causally related. Present evidence indicates that abnormalities of the short arm of No. 3 are not associated with thrombocythemia, and that patients with essential thrombocythemia have normal No. 3's. It is possible that the involved band on No. 3 contains the locus that controls megakaryocytic proliferation and platelet production. Alternatively, it may be that these translocations, which bring chromosomal material together in unusual combinations, produce either genetic activation or inactivation of one or both of the adjacent genes. Since the genetic constitution of these chromosomes is still unknown, we cannot evaluate either of these possibilities at present. The presence of nonrandom structural rearrangements, such as the 8;21 translocation in ANLL, the 15;17 translocation in APL, and the 9;22 translocation in CML, provides material for the study of the chromosomal location of genes concerned with the regulation of proliferation and maturation of bone marrow elements.
Thrombocythemia and Chromosome 3 Abnormality
37
This research was supported by the Leukemia Research Foundation, The Thomas Moore Fund, The National Foundation-March of Dimes, and an Otho S.A. Sprague Memorial Institutional Grant. Dr. Sweet is a Junior Faculty Clinical Fellow of the American Cancer Society.
REFERENCES
1. Rowley JD, Potter D: (1976): Chromosomal banding patterns in acute leukemia. Blood 47, 705-722. 2. Golomb HM, Rowley J, Vardiman J, Baron J, Locker G, Krasnow S (1978): Partial deletion of the long arm of chromosome 17; a specific abnormality in acute promyelocytic leukemia? Arch Intern Med 136, 825 -828. 3. Rowley JD, Golomb HM, Vardiman J, Fukuhara S, Dougherty C, Potter D (1977): Further evidence for a non-random chromosomal abnormality in acute promyelocytic leukemia. Int J Cancer 20, 869 - 872. 4. Testa JR, Golomb HM, Rowley JD, Vardiman JW, Sweet DL (1978)-Hypergranular promyelocytic leukemia (APL): cytogenetic and ultrastructural specificity. Blood 52, 272 - 280. 5. Rowley JD (1973): Identification of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet 16, 109 - 112. 6. Sakurai M, Sandberg AA (1975): Chromosomes and causation of human cancer and leukemia. XI. Correlations of karyotypes with clinical features of acute myeloblastic leukemia. Cancer 37, 285-299. 7. Williams WJ (1972): Examination of the bone marrow. In: Hematology, WJ Williams, E Beutier, AJ Erslev, and EW Rundles, eds. McGraw-Hill, New York, p. 26. 8. Paris Conference (1971): Standardization in human cytogenetics. Birth Defects: Original Article Series, Vol 7, No 7, The National Foundation, New York, 1972. 9. Williams WJ (1972): Thrombocytosis. In: Hematology, WJ Williams, E Beutler, AJ Erslev, and RW Rundles, eds. McGraw-Hill, New York, pp. 1162 - 1185. 10. Trujillo J, Cork A, Hart JS, George SL, Freireich EJ (1974): Clinical implications of aneuploid cytogenetic profiles in adult acute leukemia. Cancer 33,824- 834. 11. Sakurai M, Sandberg AA (1974): Chromosomes and causation of human cancer and leukemia. IX. Prognostic and therapeutic value of chromosomal findings in acute myeloblastic leukemia. Cancer 33, 1548 - 1557. 12. Golomb HM, Vardiman J, Rowley JD (1976): Acute nonlymphocytic leukemia in adults: correlations with Q-banded chromosomes. Blood 48, 9 - 21. 13. Bitran JD, Rowley JD, Plapp F, Golomb HM, Ultmann JE (1977): Chromosomal aneuploidy in a patient with hypereosinophilic syndrome: evidence for a malignant disease. Am J Med 63, 1010-1014. 14. Rowley ]D: unpublished observations. 15. Philip P (1975): A vulnerable point on human chromosome 3 in myeloproliferative disorders? Hereditas 81,124 - 125. 16. Philip P, Drivsholm A (1976): G-banding analysis of complex aneuploidy in multiple myeloma bone marrow cells. Blood 47, 6 9 - 77. 17. Altman AJ, Palmer CG, Baehner RL (1974): Juvenile "chronic granulocytic" leukemia: a panmyelopathy with prominent monocylic involvement and circulating monocyte colonyforming cells. Blood 43, 341 - 350.