1. In The name of God

2.  CD117 is a 145 kD protein tyrosine kinase also known as c- Kit.  Receptor for stem cell factor or c-Kit ligand.  CD117 is expressed on pluripotent hematopoietic progenitor cells (approximately 1-4% bone marrow cells), mast cells, and acute myeloid leukemic cells (AML).  CD117 binding of c-Kit ligand induces phosphorylation of CD117 and stimulates proliferation and survival of primitive hematopoietic stem cells as well as erythroid- committed and granulo-monocytic committed cells.

3.  Other Names: Stem cell factor receptor, c-kit, mast cell growth factor receptor, steel factor receptor  Defects in CD117 have been linked to severe anemia  The human gene for the c-kit receptor is in a region in the long arm of chromosome 4 (4q11- 4q13).

4.  BACKGROUND AND OBJECTIVE:  The CD117 molecule is an antigen more frequently found on early normal and leukemic hematopoietic cells,  its correlation with the FAB subtypes and with other lineage and stage associated antigens is still not well established.  CD117 antigen in 135 patients / acute leukemia in relationship to de novo or secondary origin of AML, subtypes of FAB classification, expression of other antigens such as CD34, HLA-DR, CD15, CD14, CD45RA, CD45RO, CD11b, CD11c, CD4, CD7, mixed antigen co- expression (LyAg + AML and MyAg + ALL) and features of leukemic mass.  DESIGN AND METHODS:  1995-1997:  82 AML (including 51 cases of de novo AML, 22 cases of AML following (MDS), 9 cases of myeloid blastic crisis -CML and 53 ALL. 

5.  RESULTS:  CD117 antigen was found over 10% in 74% of AML without significant differences of positivity between AML after MDS or BC-CML and de novo AML.  No significant correlation between FAB classification and CD117, which was expressed in 100% of M1 and M7 cases, in 80% of M0 cases, in 75% of M2 cases, in 70% of M3 cases and in 82% of M4 cases.  Instead, in M5 subtype CD117 was strictly restricted to earlier stages: ten of the eleven M5b (91%) cases completely lacked CD117 antigen expression, whereas 100% of M5a cases were positive.  a significant direct correlation between CD117 and CD34 and CD45RA (in all cases);  an independent expression between CD117 and CD15 associated with a low correlation between CD117 and HLA-DR antigen (only in non-monocytic cases).  In ALL, whether of B or T lineages, surface expression of CD117 was never observed.  CONCLUSIONS:  We conclude that the CD117 antigen shows a high specificity for AML,  independently upon FAB classification,

6.  The aim of this study was to examine the relationship between CD117 and CD34 expression on leukemic blasts and to determine whether CD117 is related to lymphoid-associated antigen (LAA) expression in AML.  BM samples were studied from cases of AML (30 cases), (MDS) (4 cases), myeloproliferative disorders in blast crisis (6 cases), and ALL (5 cases).  CD117 and CD34 were analyzed by flow cytometry.

7.  CD117/CD34 expression did not correlate with FAB subtype of AML.  CD117 is borne on most leukemic blasts of myeloid origin (in this study, 87% of AML, 80% of MPD- myeloid BC, and 75% of MDS)  Does not exclude expression of LAA.  Although CD117 is a receptor for stem cell factor, its expression does not appear to correlate with CD34 positivity.

8.  Background. The issue of which specific antibodies need to be used when evaluating acute leukemias by flow cytometry is controversial.  Methods. Recent studies have suggested that antibodies against CD117 or c-kit are not essential for the assignment of blast lineage by flow cytometry, even though CD117 appears to be a very specific marker for myeloid lineage acute leukemias.  We report a case of acute myeloid leukemia M2 subtype with an 8:21 translocation, where the leukemic blasts expressed CD117, CD19, and CD15 but did not show definitive expression of the myeloid markers CD13 or CD33.

9. It has been proposed that CD117 or c-kit expression be routinely evaluated in cases of acute leukemia because of its higher myeloid lineage specificity as compared with CD13 or CD33 However, CD117 is not as sensitive as CD13 and CD33 for identifying acute myeloid leukemias (AMLs), and recent studies have suggested that adding anti-CD117 to a flow cytometry panel that contains anti-CD13 and anti-CD33 is not essential for the assignment of blast lineage

10. 51-year-old, with a 1-month history of increasing fatigue and decreased exercise tolerance. CBC :anemia, thrombocytopenia, marked leukocytosis : 81,000 - including 27% blasts. BMA: hypercellular (95% cellularity) with an elevated myeloid to erythroid ratio (10:1) and an increased myeloid immaturity with 21% blasts. Flow cytometric :representing approximately 20% of the leukocytes with low intensity CD45 staining consistent with blasts Blasts expressed CD34, CD19, CD15, CD117, and HLA-DR without CD33 or definitive CD13.

12. Staining MPO, TdT, CD22, and CD79a :negative. Cytochemical evaluation for MPO activity showed positive-staining myeloid cells and occasional blasts but not definitive positivity on more than 3% of blasts. Nonspecific esterase staining showed only occasional positive cells. Cytogenetic :t(8;21)(q22;q22)

13. DISCUSSION Without CD117, the lack of definitive CD13 and CD33 expression with positive CD19 and CD15 staining seen in this case was more consistent with the leukemic blasts being of B cell rather than myeloid lineage. Indeed, CD19 CD10 B-lineage acute leukemias with CD15 expression are well described and often have abnormalities involving chromosome q23, e.g., balanced 4:11 translocations (5). Our finding that CD117 is sometimes essential in evaluating cases of acute leukemias by flow cytometry contrasts with the recent study by Hans et at. (3). It is well known that the contribution of flow cytometry to a diagnosis of acute leukemia is variable and can depend on what other information or data may be available. Given the marrow findings of left-shifted myeloid hyper

14. AMLs that lack CD13 and CD33 expression are rare but may account for approximately 4% of cases It is interesting that absent surface expression of CD13 and CD33 appears to be associated more frequently with the M2 subtype of AML; all four cases evaluated by Arber et al. (7) were M2- subtypes with 8:21 translocations, and three of eight cases studied by Kragulic et al. (6) were M2 subtypes. None of the CD13 and CD33 AMLs in these studies was reported to be positive for CD19, as in our case. However, approximately 80% of AMLs with 8:21 translocations are thought to express CD19 (7,8), so it is likely that additional cases of CD19 AML M2 that also lack CD13 and CD33 will be encountered by others

15. Moreover, because the sensitivity of CD117 in AML appears to be highest for the M2 subtype, which is found in approximately 80% of cases (1,3), CD117 likely will be essential when evaluating other CD19, CD13, and CD33 AML cases by flow cytometry to correctly identify the blast lineage. In conclusion: this study demonstrated that anti- CD117 antibodies are sometimes essential when evaluating AMLs by flow cytometry. In addition, this case presented an unusual AML phenotype that likely will be encountered by others and could be mistakenly thought to represent acute biphenotypic leukemia because of the CD19 expression and paucity of myeloid markers. Because CD117 is sometimes essential, it should be available for use in any flow cytometry laboratory that evaluates acute leukemias. However, because of cost and possible technical issues related to handling additional tubes, we recommend that CD117 be reserved for difficult or ambiguous cases and left out of screening or initial core panels.

16. We assessed the diagnostic usefulness of adding anti-CD117 to our existing flow cytometric profile in the analysis of 150 consecutive cases of: acute leukemia (de novo or relapsed acute myelogenous leukemia [AML], AML arising in myelodysplastic syndrome, blast crisis of chronic myelogenous leukemia [CML], acute lymphoblastic leukemia, acute unclassifiable leukemia, and biphenotypic leukemia). CD117 was expressed on more than 10% of blasts in 64% of de novo AMLs (42/66), 95% of relapsed AMLs (19/20), 75% of AMLs arising from a myelodysplastic syndrome (6/8), and 25% of myeloid blast crisis in CMLs (1/4).

17. CD117 was not expressed in acute lymphoblastic, acute biphenotypic, or unclassified leukemia or lymphoid blast crisis of CML. The specificity, positive predictive value, sensitivity, and negative predictive value of CD117 for AML were 100%, 100%, 69%, and 62%, respectively. CD117 is a specific marker for myeloblastic leukemias. Sensitivity is greatest in French-American-British M2 and relapsed AML. Intensity of CD117 expression is dim. Despite the high specificity and positive predictive value, the addition of anti-CD117 to our panel did not prove essential for the assignment of blast lineage.

18. FAB Class No. of Cases No. (%) of CD117+ Cases number of patients Number of CD 117 positive & Percentage M0 5 4 (80) M1 10 6 (60) M2 21 19 (90) M3 4 2 (50) M4 7 5 (71) M5a 2 0 M5b 5 1 (20) M7 2 1 (50)  * According to the French-American-British (FAB) classification

19. CD117 CD13 CD33 CD13 and/ or CD33 SPS: %100 86 74 64 SEN: %69 84 86 99 Positive predictive value (%) 100 /92/ 87/ 86 Negative predictive value (%) 62/ 72/ 72 /97

20.  CD117 is a specific marker for AML arising de novo or in association with myelodysplastic syndromes.  Overall, we found CD117 expression in 69% of myeloid leukemic processes (AML, MDS-AML, and CML myeloid blast crisis).  Others have reported CD117 expression by flow cytometric analysis in 23% to 91% of AML cases.  Our findings are in agreement with the largest studies that found CD117 in 63% to 67% of AML cases.  We found no CD117 expression in ALL.  Other studies have found rare examples of expression in ALL, more frequently those of T-lineage than of B-lineage.  Our study included 7 cases of T-ALL.

21.  Findings in a German cooperative study and the Children’s Cancer Group, CD117 status seems to lack prognostic significance in AML.  CD117 expression does not seem to be a reliable predictor of FAB AML subtype  Although CD117 has a high specificity, it is not as sensitive as CD13 or CD33 for detecting myeloid leukemic.  Approximately 30% of acute myeloid leukemia did not stain with anti-CD117.

22.  CD117 protein is expressed by the haemopoietic stem cells demonstrated on the primitive CD34 positive and also blasts of 30–100% of AML cases, but rarely on lymphoblasts.  Therefore several investigators have used CD117 expression to exclude lymphoblastic origin of blasts.  However, conflicting results exist in the literature.  We investigated CD34 and CD117 status at initial presentation of 232 children with acute leukemia  CD34 was commonly expressed in all types of acute leukemias, whereas CD117 molecule seemed to be a more specific marker for leukemia of myeloid origin being demonstrated on >5% of blasts in 60 out of 73 cases of AML patients, but rarely detected in ALL (9/140 patients).

23. hematopoiesis. Together with its ligand, the stem cell factor (SCF), it plays an important role in hematopoiesis. Membrane expression of CD117 can be found on leukemic blasts from approximately 60% of adult and childhood AML patients, often associated with an immature immunophenotype (CD34). Moreover, AML with t(8;21) are frequently CD117 positive. Despite earlier reports, most recent studies have not been able to demonstrate any significant prognostic impact of CD117 expression in either childhood or adult AML. A small proportion of T-lineage ALL (9%), mainly consisting of immature pro-T/pre-T-ALL, is CD117 positive. CD117 expression is rare in B-cell-precursor-ALL and occurs in less than 3% of cases..

24.  In addition to its expression in normal hematopoiesis, c-kit has been found on :  AML blasts,  as well as myeloid, erythroid, megakaryocytic and lymphoid cell lines.  Non-hematopoietic cells expressing c-kit include normal tissues such as epithelial cells of the breast, parotid and dermal sweat glands, melanocytes, central nervous system (particularly in the cerebellum, the hippocampus, and the dorsal horn of the spinal cord), placenta, interstitial cells of the testes and ovaries as well as tissues from small cell lung cancer, breast canceror melanoma, and cell lines derived from the respective tumors.

25. Most recent studies, including both childhood and adult AML, were unable to demonstrate any significant differences in CR rate, survival rate, and event-free survival between CD117-positive and CD117-negative cases. Therefore, these studies do not confirm previous results suggesting that CD117 contributes to the identification of clinically-relevant AML subgroups.