Biochemistry of Leukemia

Question 1

tumor lysis syndrome

Answer 1

occurs when large amounts of tumor cells lyse at once
-can be secondary to chemotherapy
-can be spontaneous when tumor outgrows its vascular support

Question 2

Na+/K+ ATPase

Answer 2

-maintains proper osmotic balance
-uses between 30-75% of cellular ATP

Question 3

inhibition of Na+/K+ ATPase

Answer 3

osmotic balance shifts and water flows into cells and they burst

Question 4

metabolic derangements seen in tumor lysis syndrome

Answer 4

hyperkalemia, hypocalcemia, hyperuricemia, hyperphosphatemia, high LDH

Question 5

HYPERkalemia and tumor lysis syndrome

Answer 5

-cells normally concentrate potassium
-many tumor cells lysing is delivering a potassium load to the blood

Question 6

HYPERphosphatemia and tumor lysis syndrome

Answer 6

-cells are high in phosphates (think of all the phosphorylated NTPs and every nucleotide in the genome is linked by a phosphodiester bond), so cell lysis would release a lot of phosphate

Question 7

HYPOcalcemia and tumor lysis syndrome

Answer 7

calcium cross-precipitates with phosphate, so calcium goes down (calcium-phosphate crystals)

Question 8

HYPERuricemia and tumor lysis syndrome

Answer 8

uric acid is a breakdown product of purines, and each tumor cell contains 3 billion nucleotides, so lysis of the cell causes excessive purine breakdown and therefore high uric acid

Question 9

elevated LDH (lactate dehydrogenase) and tumor lysis syndrome

Answer 9

-takes the product of glycolysis, pyruvate, and converts it to lactate
-consumes NADH and generates NAD+ to keep glycolysis going
-causes elevated lactate levels

Question 10

acute kidney injury and tumor lysis syndrome

Answer 10

excess uric acid forms crystals and clogs the kidneys, causing urate crystal nephropathy

Question 11

solubility of urate

Answer 11

-urate is not soluble above physiologic levels
-acidic environment in distal tubules and collecting ducts promotes crystal formation
-worse is that calcium-phosphate crystals increase the formation of urate crystals and vice versa

Question 12

tumor lysis syndrome prophylaxis

Answer 12

1) IV fluids (promotes clearance of metabolites)
2) allopurinol (competitive inhibitor of xanthine oxidase, inhibiting the production of urate; does not treat the crystals already formed though)

Question 13

treatment of urate crystals

Answer 13

rasburicase (converts uric acid to a more soluble form so it can be excreted in the urine)

Question 14

hydoxyurea and cytoreduction

Answer 14

inhibits ribonucleotide reductase, which stops DNA synthesis, arresting the cell in S phase

Question 15

ribonucleotide reductase

Answer 15

enzyme that catalyzes the conversion of ribonucleotides to deoyxribonucleotides, acting as the rate-limiting step in DNA synthesis; ensures a balance of the deoxyribonucletides
-active when ATP levels are HIGH
-inactive when dATP levels are high

Question 16

cytarabine treatment

Answer 16

a cytidine analogue that is S-phase specific; incorporates into the newly made DNA and blocks addition of any more nucleotides; given continuously because we need to catch cells that are actively replicating
*used as chemotherapeutic tx

Question 17

daunorubicin treatment

Answer 17

inhibits topoisomerase II (which resolves supercoils); not specific to S phase, so given by bolus

Question 18

midostaurin treatment

Answer 18

a tyrosine kinase inhibitor; blocks ATP binding to the kinase, so the mutated kinase cannot continue to phosphorylate its targets

Question 19

after a bone marrow transplant, blood from the patient would have the (donor/recipient?) karyotype

Answer 19

blood would have the DONOR’s karyotype; so if recipient is male and donor is female, then the blood sample would show a female karyotype (46, XX), even though the other cells in his body would be 46, XY