Cancer Cytogenetics - Myeloid Neoplasms

Question 1

Recite the most common cytogenetic abnormalities in AML.

Answer 1

t(8;21) - RUNX1-RUNX1T1
inv(16) or t(16;16) - CBFB-MYH11
t(15;17) - PML-RARa
t(9;11); - MLLT3-MLL(KMT2A)
t(6;9) - DEK-NUP214
inv(3) or t(3;3) - MECOM-EVI1

Question 2

AML with t(8;21):

• Abnormality?
• Epidemiology?
• Prognosis?

Answer 2

• RUNX1-RUNX1T1 (core binding factor alpha subunit)
• Found in 5% of cases, usually affecting younger patients.
• Favorable prognosis.

Question 3

AML with t(8;21):

- Morphology?

Answer 3

• Myeloblasts have abundant basophilic cytoplasm with azurophilic granules and perinuclear hofs.
• Abnormal cells have homogensous salmon-pink cytoplasm.
• Auer rods and pseudo-Chediak-Higashi granules can be seen.

Question 4

AML with inv(16) or t(16;16):

• Abnormality?
• Epidemiology?
• Prognosis?

Answer 4

• CBFB-MYH11 (core binding factor beta + myosin)
• Found in 5-8% of all AML cases, usually younger patients.
• Good prognosis

Question 5

AML with inv(16) or t(16;16):

- Morphology?

Answer 5

Bone marrow shows abnormal eosinophil component (larger basophilic granules, variable number)

Question 6

AML with t(15;17):

• Abnormality?
• Epidemiology?
• Prognosis?

Answer 6

• PML-RARa (transcription factor and retinoic acid receptor)
• 5-8% of cases, usually in “mid-life”
• Good, due to responsiveness to ATRA and arsenic trioxide.

Question 7

AML with t(15;17):

• Morphology?
• Clinical presentation?

Answer 7

• Bilobed, dumbbell-shaped nuclei with large granules & auer rods. MPO+.
• Concern for coagulopathy / DIC; a true hematologic emergency.

Question 8

What impact do CD56+ or FLT-ITD mutations have on AML with t(15;17)?

Answer 8

CD56 positivity is associated with bad prognosis.

FLT3-ITD mutations are common but do not seem to affect the prognosis.

Question 9

AML with t(9;11):

• Abnormality?
• Epidemiology?
• Prognosis?

Answer 9

• MLLT3-MLL/KMT2A (histone methyltransferase)
• Seen in ~10% of pediatric AML, 2% of adult.
• Great prognosis in children, poor prognosis in adults.

Question 10

AML with t(9;11):

- Morphology?

Answer 10

• Monoblasts and promonocytes predominate. Strongly associated with the former acute monocytic and myelomonocytic leukemias.

Question 11

AML with t(6;9):

• Abnormality?
• Epidemiology?
• Prognosis?

Answer 11

• DEK-NUP214 (DNA coiler & nuclear pore complex)
• ~1 of AML, in both adults and children.
• Poor prognosis.

Question 12

AML with t(6;9):

• Morphology?
• Clinical presentation?

Answer 12

• Basophilia. Can have auer rods and ringed sideroblasts.

- Usually presents with pancytopenia.

Question 13

AML with inv(3) or t(3;3):

• Abnormality?
• Epidemiology?
• Prognosis?

Answer 13

• EV1-RPN1 (transcriptional regulator & rER membrane protein)
• 1-2% of all AML, usually in adults
• Poor prognosis

Question 14

AML with inv(3) or t(3;3):

• Morphology?
• Clinical presentation?

Answer 14

• Atypical megakaryocytes, hypogranular neutrophils, multilineage dysplasia.
• Usually presents with anemia, less often thrombocytopenia.

Question 15

Recite the most common cytogenetic abnormalities in MDS.

Answer 15

• Deletions of 5q, 7q, 20q, and Y.

- Additions of 8.

Question 16

What cytogenetic profiles portend the best prognosis in MDS? Worst?

Answer 16

Best: -Y, del(5q), del (20q), and normal profile.
Worst: Complex, with 3+ abnormalities.

Question 17

Describe the clinical and morphologic features of MDS with isolated del(5q).

Answer 17

MDS that usually occurs in older women, with erythryoid hypoplasia and sometimes increase in megakaryocytes. Good prognosis and response to lenalidomide.

Question 18

What is the responsible gene loss in 5q- syndrome?

Answer 18

Ribosomal protein S14 (RPS14); results in abnormal erythroid and megakaryocytic differentiation.

Question 19

Describe the mechanism by which lenalidomide is efficacious in treatment of MDS with del(5q).

Answer 19

Lenalidomide induces ubiquitination of CSNK1A1 (a casein kinase), which suffers haploinsufficiency in del(5q), resulting in deletion of the tumor cells over normal.

Question 20

Describe the translocation chiefly responsible for CML.

Answer 20

t(9;22)(q34;q11.2); BCR-ABL1

Question 21

What features are characteristic of neoplasms with rearrangements of PDGFRa/b and FGFR1?

Answer 21

Neoplasms arise from an aberrant tyrosine kinase with characteristic eosinophilia. Usually presents as MPN, but can also manifest as lymphoid.