scholarly journals Patient-derived acute myeloid leukemia (AML) bone marrow cells display distinct intracellular kinase phosphorylation patterns

2009 ◽  
pp. 49
Author(s):  
Michael Lahn
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Kinase Phosphorylation ◽  
Acute Myeloid ◽  
Marrow Cells

The Growth Inhibition and Apoptosis Induction of Acute Myeloid Leukemia Blast Population by the Blocking IGF-IR Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4515-4515
Author(s):  
Si Sun ◽  
Yanli He ◽  
Xingbing Wang ◽  
Wei Liu ◽  
Jun Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Pi3k Pathway ◽  
Leukemia Cell Line ◽  
Free System ◽  
Acute Myeloid ◽  
Marrow Cells

Abstract The insulin-like growth factor-1receptor (IGF-1R) is overexpressed in a variety of tumors and has been associated with cancer development. Here, we analysis the IGF-IR expression on the bone marrow cells from 45 newly diagnosed patients with acute myeloid leukemia (AML) by flow cytometry. IGF-1R universally expressed on AML blasts and the leukemia cell line HL-60, did not show significant correlation with FAB subtypes. However, the bone marrow cells from AML patients with high myeloblast counts (>80%) generally showed brighter IGF-IR expressions, which indicated the IGF-IR pathway might play an important role for AML blast proliferation and survival. Indeed, blocking the IGF-1R pathway by neutralizing monoclonal antibodies could reduce the proliferation of HL-60 cells by 38.28% at 48 hr. This inhibitory effect on blast growth was observed in 4 of 5 AML samples. In the same IGF-1R blocking treatment, the apoptosis of HL-60 cells was significantly induced, resulting in apoptosis of 57% of the cell population with the measurement of Annexin V vs PI staining by flow cytometry. The control contained only 20% apoptotic cells. We also demonstrated that the blockade of the IGF-1R pathway inhibited the phophorylation of the PI3K pathway component Akt in HL-60 cells when cultured in a serum free system with a supplement of 50ng/ml exogenous IGF. Since PI3K pathway activation greatly contributes to the proliferation, survival and drug resistance of AML, it is of interest to study whether blockading IGF-IR could also inhibit the PI3K pathway in primary AML blasts and synergize other anti-leukemia agents to improve the therapeutic effectiveness. Conclusions: IGF-IR may play an important role in the proliferation and survival of the AML blast population; Blocking the IGF-IR pathway could significantly inhibit the growth of AML blasts and considerably induce the apoptosis of AML blasts; IGF-IR could become a critical molecular target in anti-leukemia drug discovery.

Acute Myeloid Leukemia Cells Generate Leukemic Endothelial Cells with Leukemogenic Potential: Blood Vessels As Sanctuaries for Leukemia Relapse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 241-241
Author(s):  
Christopher R Cogle ◽  
Gerard J Madlambayan ◽  
Devorah C Goldman ◽  
Azzah Al Masri ◽  
Ronald P. Leon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Endothelial Cell ◽  
Blood Vessels ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Surface Proteins ◽  
Nsg Mice ◽  
Acute Myeloid ◽  
Marrow Cells

Abstract Abstract 241 Human hematopoietic stem cells (HSCs) possess hemangioblast activity, which is defined as the ability to generate both blood and endothelium. Whether malignant HSC counterparts such as acute myeloid leukemia (AML) also display this bipotentiality remains to be defined. To test the hemangioblast potential of AML cells we first cultured primary human AML bone marrow in conditions established by Yoder and colleagues that support the growth of functional endothelial cell (EC) progenitors. AML cultured in endothelial colony forming cell (ECFC) media generated endothelial progenitor cell colonies that showed uptake of acetylated LDL and expressed several EC surface proteins, including CD105, CD146, UEA-1 and CD144. Importantly, ECFCs derived from AML bone marrow no longer expressed CD45 or myeloid surface proteins such as CD14. When placed in Matrigel, these AML derived ECFC generated capillary-like, tubular structures. Moreover, these ECFCs contained cytogenetic mutations associated with their parental leukemias. Thus, under the appropriate conditions, AML bone marrow cells can generate cells with an endothelial-like phenotype and harboring leukemia specific mutations that will be referred to as ‘L-ECFC.' To functionally define leukemia hemangioblast activity, a xenograft model of AML was employed. Sublethally irradiated NOD/scid/IL2Rγ−/− (NSG) mice were transplanted with primary human AML cells and then sacrificed at 8–36 weeks after transplant. Significant accumulations of human AML cells were found in perivascular regions of the liver. Both tight coupling and bona fide cell fusion between AML and ECs was observed. AML derived EC that were integrated into portal vein endothelium showed induction of CD105 expression Follow-up AML xenotransplant experiments with BrdU labeling revealed almost four-fold fewer (6%) of the AML cells incorporated within blood vessels were BrdU+, as compared to AML cells not integrated in blood vessels (22%) (P=0.01). These results suggest that AML cell incorporation within the endovascular lining induces cell quiescence. Thus, leukemia-integrated ECs may be less susceptible to cell cycle active agents like cytarabine. Results from these experiments also raised the possibility that AML cells adopting an endothelial-like phenotype may serve as a reservoir for leukemic relapse. To test this hypothesis, we injected CD105+CD45- L-ECFC derived from AML patients into NSG mice. These L-ECFC generated colonies of human CD105+CD45- within spleens and bone marrow of recipient mice. We also found a distinct population of human CD45+CD19- cells comprising 5–10% of bone marrow cells. Leukemia-derived cells were confirmed by detection of cytogenetically mutant cells consistent with the parent leukemia (e.g., MLL duplications). In conclusion, this study demonstrates that AML cells can functionally generate leukemic ECs that become quiescent after incorporation in blood vessel networks and can re-emerge with a leukemogenic phenotype. Together, our results raise the strong possibility that AML cells exhibit functional hemangioblast activity and that vascular endothelium may serve as a clinically important sanctuary for occult leukemia. Our data also support endothelial cell targeting strategies as a means to eradicate AML. Disclosures: No relevant conflicts of interest to declare.

t(6;9) in bone marrow cells in two patients with sarcoidosis and acute myeloid leukemia

1989 ◽  
Vol 38 (2) ◽  
pp. 297-300 ◽  
Author(s):  
I. Nordenson ◽  
L. Bjermer ◽  
G. Holmgren ◽  
P. Hörnsten ◽  
A. Wahlin
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Acute Myeloid ◽  
Marrow Cells

Continued Expression of the NRAS(G12V) Oncogene Is Required for the Maintenance of Acute Myeloid Leukemia Induced in Cooperation with MLL-AF9.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1615-1615
Author(s):  
Won-Il Kim ◽  
Ilze Matise ◽  
Miechaleen Diers ◽  
David Largaespada
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Transgenic Mice ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Scid Mice ◽  
Myeloid Lineage ◽  
Blast Cells ◽  
Acute Myeloid ◽  
Marrow Cells

Abstract To study the role of the NRAS(G12V) oncogene in the context of acute myeloid leukemia (AML) cells developing with in cooperation with MLL fusion oncogene (MLL-AF9), we used a Vav promoter-Tet transactivator (Vav-tTA)-driven repressible system of NRAS(G12V) expression in Mll-AF9 mice. Vav-tTA; TRE-NRAS(G12V); Mll-AF9 triply-transgenic mice were generated by crossing the Vav-tTA; TRE-NRAS(G12V) doubly-transgenic FVB/n and Mll-AF9 knock-in BL6 mice. The triply-transgenic FVB/n × BL6 F1 mice expressing both the NRAS(G12V) and Mll-AF9 transgenes developed AML, which showed a trend of decreased latency compared with those carrying only the Mll-AF9 knock-in transgene. Mast cell disease also occurred accordingly in the Vav-tTA; TRE-NRAS(G12V) co-transgenic mice. Since the mastocytosis disease is not transplantable, we transplanted bone marrow cells from four independent AML mice into recipient SCID mice to determine whether NRAS(G12V) expression is necessary to maintain AML in the recipient mice without mastocytosis. Continuously treating the transplanted SCID mice with doxycycline (Dox) in drinking water, we found the expression of NRAS(G12V) oncogene was required for AML persistence in three out of the four independent primary AML cells. Furthermore, we transplanted the AML bone marrow cells previously xenografted in the recipient SCID mice into other SCID mice to conditionally repress NRAS(G12V) expression only after the transplanted AML was fully established. We found the number of WBC cells was greatly decreased 4–6 days after the Dox treatment and this was correlated with the significant increase of apoptotic cells in bone marrow and peripheral bloods. The transplanted AML blast cells underwent apoptosis and were mostly removed from the circulating blood, bone marrow, and spleen after 8 days post Dox treatment. In 2–3 weeks after beginning Dox treatment and observing AML remission, Dox-resistant leukemia relapse was observed in recipient SCID mice. The relapsed leukemia failed to express NRAS(G12V) and showed significantly reduced aggressiveness along with less myelosuppression and more differentiated myeloid lineage cells than AML prior to repression of NRAS(G12V) expression. The NRAS(G12V)-independent relapsed disease histopathologically resembles an aggressive myeloproliferative disease (MPD) rather than AML, because the proportion of AML blast cells was less than 20% of myeloid lineage cells. The NRAS(G12V)-independent MPD could be transplanted into recipient SCID mice, but the subsequent anemia was greatly attenuated compared to transplant of the same AML clone expressing NRAS(G12V). We conclude that NRAS(G12V) can be a good molecular target to treat AML, because NRAS(G12V) expression is required for persistence and specific malignant features in AML induced in cooperation with MLL-AF9. Targeting NRAS(G12V) can strongly disturb the maintenance of AML blast cells and myelosuppression, although leukemia cells can relapse without NRAS(G12V) expression.

Direct versus cultured preparation of bone marrow cells from 22 patients with acute myeloid leukemia

1982 ◽  
Vol 60 (3) ◽  
pp. 281-283 ◽  
Author(s):  
Peter H. Fitzgerald ◽  
Christine M. Morris ◽  
Lynette M. Giles
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Acute Myeloid ◽  
Marrow Cells
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