SEVERE COMBINED IMMUNODEFICIENCY ASSOCIATED WITH ACUTE MYELOID LEUKEMIA

Primary bone marrow blasts from 4 children with t(8;21) acute myeloid leukemia (AML), 6 children with inv(16) AML, and 2 children with t(9;11) AML were injected intravenously or transplanted under the kidney capsule of sublethally irradiated mice with severe combined immunodeficiency (SCID). Leukemic cells from all AML patients infiltrated the SCID mouse thymus, suggesting that the thymic microenvironment supports the survival and growth of human AML blasts. Blasts from 1 of 4 t(8;21) AML patients and 4 of 6 inv(16) AML patients caused histopathologically detectable disseminated leukemia. Blasts from the remaining patients produced disseminated occult leukemia that was only detected by polymerase chain reaction. Occurrence of histopathologically detectable disseminated leukemia was dependent on intravenous injection of leukemic cells; none of the mice challenged with an inoculum transplanted under the kidney capsule developed overt leukemia. No obvious association was noted between occurrence of leukemia in SCID mice and clinical or laboratory features presented by patients, including age, sex, or leukocyte count at diagnosis. To our knowledge, this study is the first to show that leukemic blasts from children with newly diagnosed AML, especially inv(16) AML, can cause disseminated human leukemia in SCID mice without exogenous cytokine support. The SCID mouse model system may prove particularly useful for designing more effective treatment strategies against childhood AML.

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Childhood acute myeloid leukemia in mice with severe combined immunodeficiency

Blood ◽

10.1182/blood.v84.1.20.20 ◽

1994 ◽

Vol 84 (1) ◽

pp. 20-26 ◽

Cited By ~ 11

Author(s):

LM Chelstrom ◽

R Gunther ◽

J Simon ◽

SC Raimondi ◽

R Krance ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Scid Mouse ◽

Severe Combined Immunodeficiency ◽

Scid Mice ◽

Leukemic Cells ◽

Human Leukemia ◽

Combined Immunodeficiency ◽

Kidney Capsule ◽

Acute Myeloid

Abstract Primary bone marrow blasts from 4 children with t(8;21) acute myeloid leukemia (AML), 6 children with inv(16) AML, and 2 children with t(9;11) AML were injected intravenously or transplanted under the kidney capsule of sublethally irradiated mice with severe combined immunodeficiency (SCID). Leukemic cells from all AML patients infiltrated the SCID mouse thymus, suggesting that the thymic microenvironment supports the survival and growth of human AML blasts. Blasts from 1 of 4 t(8;21) AML patients and 4 of 6 inv(16) AML patients caused histopathologically detectable disseminated leukemia. Blasts from the remaining patients produced disseminated occult leukemia that was only detected by polymerase chain reaction. Occurrence of histopathologically detectable disseminated leukemia was dependent on intravenous injection of leukemic cells; none of the mice challenged with an inoculum transplanted under the kidney capsule developed overt leukemia. No obvious association was noted between occurrence of leukemia in SCID mice and clinical or laboratory features presented by patients, including age, sex, or leukocyte count at diagnosis. To our knowledge, this study is the first to show that leukemic blasts from children with newly diagnosed AML, especially inv(16) AML, can cause disseminated human leukemia in SCID mice without exogenous cytokine support. The SCID mouse model system may prove particularly useful for designing more effective treatment strategies against childhood AML.

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Acute Myeloid Leukemia in a Patient With X-linked Severe Combined Immunodeficiency

Journal of Pediatric Hematology/Oncology ◽

10.1097/mph.0000000000000892 ◽

2017 ◽

Vol 39 (8) ◽

pp. e470-e472

Author(s):

Tomonari Shigemura ◽

Mitsuo Motobayashi ◽

Kazuyuki Matsuda ◽

Takahiro Shimodaira ◽

Takashi Kurata ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Severe Combined Immunodeficiency ◽

Combined Immunodeficiency ◽

Acute Myeloid

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Hoechst 33342 efflux identifies a subpopulation of cytogenetically normal CD34+CD38− progenitor cells from patients with acute myeloid leukemia

Blood ◽

10.1182/blood.v97.12.3882 ◽

2001 ◽

Vol 97 (12) ◽

pp. 3882-3889 ◽

Cited By ~ 78

Author(s):

Michaela Feuring-Buske ◽

Donna E. Hogge

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Side Population ◽

Severe Combined Immunodeficiency ◽

Hoechst 33342 ◽

Nonobese Diabetic ◽

Abnormal Cells ◽

Hoechst Dye ◽

Mdr 1 ◽

Acute Myeloid

Efflux of Hoechst 33342 from normal hematopoietic cells identifies a “side population” (SP+) of negatively staining cells that, in the mouse, are largely CD34− and are enriched for primitive progenitors. To further characterize human SP+cells, blood or bone marrow from 16 patients with acute myeloid leukemia (AML) was analyzed for their presence, immunophenotype, and cytogenetic and functional properties, and for the relation between SP phenotype and multidrug resistance-1 (MDR-1) expression. The mean percentages of SP+ and MDR+ cells was 8.1% (range, 0.5%-29.9%) and 12.8% (range, 0%-54.8%), respectively, with no correlation between the 2 values. The percentages of SP+ cells that were CD34+CD38−, CD34+CD38+, or CD34− were 12% (range, 0.4%-50%), 25% (range, 0.5%-96%), and 63% (range, 4%-99%). Cytogenetically abnormal cells were always detected in the SP−CD34+CD38− and SP+CD34− fractions, and abnormal colonies (CFC), long-term culture-initiating cells (LTC-IC), and nonobese diabetic-severe combined immunodeficiency (NOD/SCID) mouse leukemia–IC were detected in the former fraction. No progenitors were detected among SP+CD34− cells in any of these assays from 9 of 10 samples. In contrast, exclusively normal cells were detected in the SP+CD34+CD38−fraction from 9 of 15 samples, and CFC, LTC-IC, and multilineage engraftment in NOD/SCID mice from this subpopulation were also cytogenetically normal in 6 of 8, 6 of 7, and 2 of 2 cases studied, respectively. In contrast to murine studies, primitive progenitors are enriched among SP+CD34+CD38− cells from patients with AML. The molecular basis for Hoechst dye efflux is uncertain because it does not appear to be related to MDR-1 expression.

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Fluorouracil selectively spares acute myeloid leukemia cells with long- term growth abilities in immunodeficient mice and in culture

Blood ◽

10.1182/blood.v88.6.1944.bloodjournal8861944 ◽

1996 ◽

Vol 88 (6) ◽

pp. 1944-1950 ◽

Cited By ~ 74

Author(s):

W Terpstra ◽

RE Ploemacher ◽

A Prins ◽

K van Lom ◽

K Pouwels ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Severe Combined Immunodeficiency ◽

Scid Mice ◽

Leukemic Cells ◽

Human Leukemia ◽

Hematopoietic Stem ◽

Acute Myeloid

A subset of leukemic cells is assumed to maintain long-term growth of acute myeloid leukemia (AML) in vivo. Characterization of these AML progenitor cells may further define growth properties of human leukemia. In vitro incubations with 5-fluorouracil (5-FU) have been used for enrichment of normal primitive hematopoietic stem cells. By analogy to normal hematopoiesis, it was hypothesized that primitive leukemic stem cells might be kinetically more inactive than colony- forming cells (colony-forming units-AML [CFU-AML]). To examine this hypothesis, conditions were established for incubation with 5-FU that eliminated all CFU-AML. These conditions selected a 5-FU-resistant AML fraction that was evaluated for its capacity for long-term growth by transplantation into mice with severe combined immunodeficiency (SCID) and long-term culture in the quantitative cobblestone area-forming cell (CAFC) assay. Transplantation of the 5-FU-resistant fraction of four cases of AML into SCID mice resulted in growth of AML. Whereas no CFU- AML survived, 31% to 82% of primitive (week-6) CAFC were recovered from the 5-FU-treated cells. Hematopoietic cells proliferating in the CAFC assay were shown to be leukemic by cytologic, cytogenetic, or molecular analysis. The reduction of AML growth as determined by outgrowth of AML in SCID mice was in the same order of magnitude as the primitive (week- 6) CAFC reduction. This indicates that both assays measure closely related cell populations and that the CAFC assay can be used to study long-term growth of AML. These results show a hierarchy of AML cells that includes 5-FU-resistant progenitors. These cells are characterized as primitive (week-6) CAFC and as leukemia-initiating cells in SCID mice.

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